Fabulous Fluorine

Fluorine can be highly advantageous in pharmaceutical and agrochemical compounds. One or just a few atoms in an organic molecule can dramatically alter its chemical and biological nature, including its stability, lipophilicity, and bioavailability. As many as 30−40% of agrochemicals and 20% of pharmaceuticals on the market are estimated to contain fluorine, including half of the top 10 drugs sold in 2005. Developmental pipelines are predicted to contain even more.

"Smuggling fluorine into a lead structure enhances the probability of landing a hit almost 10-fold" is a rule of thumb in medicinal chemistry, says Manfred Schlosser, professor of chemistry at the Swiss Federal Institute of Technology, Lausanne. Few organofluorine compounds exist naturally (C&EN, May 22, page 12), meaning that almost all must be made. But getting fluorine into a molecule easily, selectively, and safely presents synthetic challenges.

Two major approaches have emerged: One is to introduce fluorine or a fluorinated moiety at an appropriate stage during synthesis, while the other starts with a fluorine-containing building block as the basis for further conversions (see page 27). The merits and drawbacks of either technique can depend on the substrate, target, fluorination sequence, and subsequent synthetic steps. In manufacturing, material availability, cost, and safety are considerations as well.

Organofluorine chemistry differs from traditional organic synthesis, remarks University of Florida chemistry professor William R. Dolbier Jr. in a brief overview (J. Fluorine Chem. 2005, 126, 157). "Oftentimes, a fluorine atom isn't noticed in terms of size, yet it can have a really strong impact," he tells C&EN about fluorine's unique effects on reactivity. Fluorinated groups are isosteres of many common substituents, and fluorine can play various roles in affecting activity. "Every time you see a biologically active molecule that has fluorine in it, it could be in there for a different reason."

To meet a growing demand for fluorinated structures, custom chemical firms with experience handling hazardous reagents, such as elemental fluorine, sulfur tetrafluoride, and hydrogen fluoride, suggest "leaving the synthesis to us," especially on an industrial scale. But researchers now have many more benign fluorinating reagents at their disposal or can use tools such as microreactors to control reactions (C&EN, Feb. 14, 2005, page 35). Nevertheless, there's still a gap between the lab and the plant.

Large-scale synthesis of fluorinated intermediates is dominated by electrofluorination; diazotization with NaNO₂ and HF; halogen exchange (Halex) with HF or KF; and direct fluorination with F₂, rather than the use of more easily handled, but expensive, reagents. Pharmaceutical and agrochemical producers often outsource production to companies with the required expertise and equipment. Providers include those that have fluorine chemistry capabilities among their tools for custom synthesis, others that specialize in fluorination technologies, and those that are leveraging an existing base in fluorinated products.

"More than 15 or 20 years ago, when you added fluorine to an organic molecule, you'd more than likely end up with a fire or explosion and a completely unselective process," says Martin Greenhall, R&D manager at F2 Chemicals. The company has developed selective direct fluorination for the controlled use of F₂ for fluorinating aliphatic, aromatic, and sulfur-containing compounds. "If you choose the conditions and substrate correctly, you can minimize the free radical chemistry and instead get fluorine acting mostly as electrophilic F⁺ and very selectively fluorinating just one or two among any number of sites."

Clariant uses direct fluorination to produce the anticancer agent 5-fluorouracil at large scale for multiple customers. Developed in the 1950s, the drug, along with fluorinated steroids and anesthetics, is considered among the early milestones in medical applications of fluorinated compounds. The company uses elemental fluorine late in the synthesis to make the drug under current Good Manufacturing Practice (cGMP) conditions.

Doing so can be risky, since along with possible unselective reactions, the extremely reactive gas can tear apart valuable molecules. But under highly controlled conditions, the approach gives the best results for making the active ingredient, according to Ralf Pfirmann, global business director for Clariant's pharmaceutical fine chemicals business. It's also, he believes, "probably the only Food & Drug Administration-approved direct fluorination in the world."

Waiting until the cGMP stage of active ingredient manufacture is the exception, agrees Marc Thommen, project leader for custom synthesis at Solvias. The chemoselectivity issues associated with fluorination, which often doesn't tolerate a lot of functional groups, can result in by-products and lost yield. "If you have a complex entity, putting a fluorine in the middle of it without touching everything else is a huge challenge," he says.

Instead, customers typically outsource small pieces of their synthetic processes to have fluorine put in before they continue building their molecule, he explains. They also usually start thinking about the fluorinated structures they need early in the lead optimization or medicinal chemistry stage.

To compete, many custom chemical firms combine fluorination capabilities with other technologies. Solvias, for example, offers a range of custom synthesis tools and in the fluorination area specializes in the modified Schiemann reaction for converting anilines to fluoroaromatics with diluted F₂ gas, deoxofluorinations that use SF₄ and HF to introduce trifluoromethyl groups, and enantioselective fluorination reactions.

Solvias also offers Halex reactions, as do Clariant, Saltigo (the Lanxess fine chemicals unit), and Shasun Pharma Solutions (part of the former Rhodia pharma business). This method is commonly used to make fluoroaromatics on an industrial scale. It typically starts with chloroaromatics-activated toward nucleophilic substitution by electron-withdrawing groups-that are reacted with a fluoride source, often KF, at high temperature.

A goal is to create unique substitution patterns, some of which have been accomplished through solvent changes and use of spray-dried fluorides. Saltigo and Clariant boast new phase-transfer catalysts for Halex reactions on unactivated rings, such as 1,3,5-trichlorobenzene. The catalysts increase the solubility of the fluoride salt and thereby improve reaction rates. Saltigo's catalysts are 2-azallenium compounds, whereas Clariant uses amidophosphonium salts.

Anhydrous HF also can exchange with chlorine to form trifluoromethyl and trifluoromethoxy groups. Although versatile for reactions at benzylic positions or in aliphatics, the approach is limited by the acidity of HF and undesirable side reactions in fragile or functionalized molecules. Laurent Saint-Jalmes, while at Rhodia, found that HF-base media, specifically HF-amines, give mild enough conditions for these reactions (J. Fluorine Chem. 2006, 127, 85).

Recently, chemistry professor Stephen G. DiMagno at the University of Nebraska, Lincoln, has used tetrabutylammonium fluoride (TBAF) for Halex and fluorodenitration reactions (Angew. Chem. Int. Ed. 2006, 45, 2720). His group found that anhydrous TBAF in dimethylsulfoxide works well under mild conditions as a fluorinating reagent for activated ring systems.

Although they can handle worse, industrial researchers still search for more stable and less toxic fluorinating reagents. Saltigo has Fluorinox, a class of difluoroamines it optimizes in custom syntheses to substitute fluorine for a hydroxyl group or to convert carbonyls into geminal difluorides. Fluorinox is milder than diethylaminosulfur trifluoride (DAST), a reagent developed 30 years ago, says Wolfgang Ebenbeck, head of Saltigo's fluorine team. DAST is made from very toxic and corrosive SF₄ and decomposes spontaneously, he remarks, "so you wouldn't use it in a scaled up process."

Saltigo has for the first time scaled up a fluorination reaction using perfluoro-1-butanesulfonyl fluoride (PBSF). Lanxess makes several metric tons per year of the nontoxic, easily handled reagent. 3M also produces PBSF and makes it available on an experimental basis. "We are using PBSF in the stereoselective substitution of an alcohol by fluorine," on a highly functionalized chiral substrate, Ebenbeck says. After optimizing conditions to avoid elimination or racemization by-products, the yield was increased to about 80%; Saltigo now runs the reaction at the ton scale.

Alternatives to or improved versions of traditional fluorination reagents are also being developed by companies with fluorine chemistry expertise. The early fluorinating reagent pyridinium poly(HF), or Olah's reagent, was discovered by Nobel Laureate George A. Olah in the late 1970s. Since then, many other nitrogen-based structures have emerged; with the general form R₂N−F or R₃N⁺−F, they are often called the N-F or [N-F]⁺ reagents, respectively.

Daikin Industries offers several derivatized pyridinium compounds in lab and bulk scale, including N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) or MEC-31, also sold as SynFluor by SynQuest Laboratories. Tosoh F-Tech's F-Plus pyridinium salts vary as well in substituents and counter anions. These electrophilic reagents are more selective than F₂ and, depending on their structure, have moderate to high fluorinating ability without requiring low temperatures to control reactions, explains Robert J. Byron, business development manager for Tosoh USA.

Similarly, there are decades-old fluoroalkylamine reagents (FAR), such as the Yarovenko reagent [N-(2-chloro-1,1,2-trifluoroethyl)diethylamine] and the Ishikawa reagent (N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine) for nucleophilic fluorinations, which introduce fluorine as F^-. Tosoh has developed related FARs in response to evolving market needs, Byron says. The company uses them in-house in industrial-scale syntheses of optically pure fluoroproline derivatives as drug and agrochemical building blocks.

DuPont, like Tosoh and others, leverages a position in fluoroorganics and fluoroproducts to develop fluorinating reagents. DuPont makes N,N-dimethyl-1,1,2,2-tetrafluoroethylamine (TFEDMA), the dimethylamine adduct of tetrafluoroethylene (TFE), available on a research scale. Like that of other fluoroalkylamines, its utility is in fluorodehydroxylation reactions, but it has the advantage of a water-soluble by-product, says Allen C. Sievert, DuPont senior research associate.

Honeywell, a major HF producer, makes TBAF, Accufluor (1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), and N-fluorobenzenesulfonimide (NFSI). Mitsui Chemicals, which makes fluorinated materials for electronics applications, also sells 2,2,-difluoro-1,3-dimethylimidazolidine (DFI), which exchanges hydroxyl groups and carbonyls for fluorine, as a low-cost and more stable alternative to DAST.

Air Products & Chemicals produces SF₄ and many other inorganic fluoride gases for electronics applications. About 10 years ago it developed Selectfluor, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), in collaboration with chemistry professor Eric Banks at the University of Manchester, in England.

Selectfluor, also known as F-TEDA-BF₄ (other derivatives with different reactivities are possible), is a widely used fluorinating reagent and the subject of many articles and reviews (Angew. Chem. Int. Ed. 2005, 44, 192; Acc. Chem. Res. 2004, 37, 31). It is considered a good alternative to harsher methods, especially for high-value compounds. The electrophilic reagent acts essentially as a stoichiometric source of F⁺ and can fluorinate specific positions in a range of substrates.

Air Products also developed Deoxo-Fluor, bis(2-methoxyethyl)aminosulfur trifluoride, a less thermally sensitive variant of DAST that converts alcohols, aldehydes, and ketones more safely. "Selectfluor and Deoxo-Fluor were created to deliver fluorine to the pharmaceutical industry through a safe and effective material," says John Caligiuri, business development manager for fluorine reagents at Air Products.

"Pharmaceutical chemists don't like to use gases because they are hard to store and hard to measure into reactors consistently," he adds. Although care in handling is needed, the company says, Deoxo-Fluor is an easy-to-use, stable liquid that is cost-efficient and more amenable than DAST to large-scale applications. Similarly, Selectfluor consists of thermally stable, free-flowing crystals. The company makes both in "multi-metric-ton-per-year quantities."

Although the N-F and other reagents can have good reactivity and high selectivity, they have limitations. Some are costly or difficult to make, and others, such as the powerful electrophilic reagent N-fluorobis[(trifluoromethyl)sulfonyl]imide, are not commercially available. Yet others don't show enough fluorinating power to make them useful, are limited in scope, or are problematic in handling, even producing by-products such as HF.

"Quite of lot of fluorinated compounds can be produced using fluorinating reagents, and there have been huge developments over the past 20 years," F2 Chemicals' Greenhall says. "The problem for large-scale use is that they are often made from fluorine anyway-so first you have to make the reagent, add it to your substrate, and then separate the remains of the reagent from the product." Direct fluorination, he adds, is a shortcut directly from substrate to product.

The fluorination route ultimately used can depend on the scale of the reaction, explains Marc A. Rotteveel, business director for marketing and new business development at Tosoh Europe. "Fluorinating reagents are sometimes quite expensive, and there is a ceiling for the optimum in economics and efficiency," he explains. Tosoh may propose, once a customer has identified a target compound in a lab synthesis, "that they give us the molecule and we'll use selective direct fluorination with F₂ gas to make it in a more economic way," he says.

On a lab scale, however, fluorinating reagents offer a beneficial middle ground between using building blocks and direct fluorination. "Having a fluorinated group present at a very early stage in a synthetic sequence can cause problems because it affects the reactivity of the adjacent functional groups," says Véronique Gouverneur, university lecturer in chemistry at Oxford University. "With direct fluorination, you need to control chemo-, regio-, diastereo-, and enantioselectivity."

Gouverneur is interested in using ¹⁸F, which has a 110-minute half-life, as a positron emission tomography probe and thus focuses on adding fluorine late in a synthesis. "In the past few years, having fluorinating reagents of 'tuned' or differential reactivity has been the major advance allowing so much more work on late fluorination and on catalytic enantioselective fluorination," she says. "This work wouldn't have been possible if the right reagents were not available."

Although still challenging, asymmetric fluorination is an area that has undergone rapid changes due to the desirability of both chiral and fluorinated compounds, Dominique Cahard and Jun-An Ma at the University of Rouen, in France, pointed out in reviewing the field (Chem. Rev. 2004, 104, 6119), as has Gouverneur more recently (Org. Bio. Mol. Chem. 2006, 4, 2065). Early methods relied on substrate-controlled stereoselective fluorinations or substitutions. Then came reactions in which chiral stoichiometric reagents generated stereogenic centers in achiral substrates. More recently, transition-metal catalysts and organocatalysts have emerged for enantioselective reactions.

In 1988, Edmond Differding and Robert W. Lang, at what was then Ciba-Geigy, conducted the first enantioselective electrophilic fluorination under reagent control, using chiral N-fluorocamphorsultams to fluorinate enolates. Subsequently, Franklin A. Davis at Temple University looked at modified fluorosultams, while Japanese researchers developed other chiral N-F reagents, including sulfonamides. Drawbacks were the multistep synthesis of the reagents from F₂ or perchloryl fluoride, low selectivities, and limited substrate scope.

A major step, taken in 2000 both by Cahard's group and by Yoshio Takeuchi, Norio Shibata, and others then at Toyama Medical & Pharmaceutical University in Japan, was to combine Selectfluor with chiral cinchona alkaloids. The two groups tested these reagents successfully on enolates, silyl enol ethers, β-ketoesters, β-cyanoesters, and oxindoles. Later, Cahard's group tested them on amino acid derivatives and dipeptides. Cahard and Shibata also separately reported syntheses of Bristol-Myers Squibb's fluorooxindole drug MaxiPost (Org. Biomol. Chem. 2003, 1, 1833; J. Org. Chem. 2003, 68, 2494).

Chiral fluorinating agents have shown the most general applicability, but catalytic methods are attractive. "Hopefully, there will be some new ideas coming in the next few years," says Antonio Togni, chemistry professor at the Swiss Federal Institute of Technology, Zurich, whose group achieved the first catalytic enantioselective electrophilic fluorination (Angew. Chem. Int. Ed. 2000, 39, 4359). They found that Selectfluor in the presence of titanium complexes can fluorinate β-ketoesters in high yield and with high enantiomeric excess. Solvias now has rights to this technology.

Since then, many researchers have weighed in with other transition-metal catalyst/fluorinating reagent combinations. Mikiko Sodeoka's group, now at RIKEN, in Japan, worked with palladium complexes. Using bis(oxazoline) complexes, Cahard looked at copper, Shibata and coworkers used nickel, and Karl Anker Jørgensen's group at Aarhus University, in Denmark, worked with zinc. Shibata and colleagues also used a Ni complex in the first catalytic enantioselective preparation of MaxiPost (Angew. Chem. Int. Ed. 2005, 44, 4204).

Junji Inanaga at Kyushu University, in Japan, and colleagues recently explored chiral rare earth metal complexes with fluorinated organophosphate ligands in the enantioselective fluorination of β-ketoesters (Tet. Asym. 2006, 17, 504). "Previously published methods have been applied to bulky esters," Inanaga says, "while ours can be applied to popularly used small esters, such as methyl ester." Using a scandium catalyst in combination with a 1-fluoropyridinium triflate fluorinating reagent, the researchers achieved yields as high as 94% with 84% enantiomeric excess (ee).

Togni recently used chiral ruthenium complexes for catalytic enantioselective fluorination (Pure Appl. Chem. 2006, 78, 391). Despite the past successes, catalytic enantioselective fluorination has been limited to 1,3-dicarbonyls and β-ketophosphonates. The substrate scope is still quite limited, with carbonyls being needed to coordinate to the metal catalysts, he explains. "There is still a lot of work to do. It's not like asymmetric hydrogenation, where you can find hundreds of examples."

Meanwhile, Dae Young Kim and coworkers at South Korea's Soonchunhyang University used phase-transfer catalysis with chiral quaternary ammonium salts to fluorinate β-ketoesters. Much less common are attempts at stoichiometric and catalytic enantioselective nucleophilic fluorination. In 1989, Gerald L. Hann and Paul Sampson at Kent State University synthesized a chiral analog of DAST and used it to resolve racemic ethyl (2-trimethylsiloxy)propanoate by enantioselective fluorodehydroxylation; the enantiomeric excess, however, was just 16%.

One of the newest developments has been organocatalyzed enantioselective fluorination reactions, Togni says. Over just a few weeks in 2005, the labs of Jørgensen; David W. C. MacMillan at California Institute of Technology; Carlos F. Barbas III at Scripps Research Institute; and Dieter Enders at the Institute of Organic Chemistry, in Aachen, Germany, all reported on the α-fluorination of aldehyde substrates using Selectfluor or NFSI with chiral amine catalysts.

"The organocatalysts can address monocarbonyls, and the potential of this methodology from a synthetic point of view is probably broader," Togni says. "But overall, synthetically useful enantioselective approaches are rare, and there is still no methodology to α-fluorinate any other type of functional group or catalytically fluorinate a nonactivated molecule chemo-, regio-, and stereoselectively."

Although there have been attempts to α-fluorinate ketones, the reaction has proven problematic. In light of this, Shibata, Takeshi Toru, and coworkers at Nagoya Institute of Technology, in Japan, decided to explore a catalytic, rather than the typical stoichiometric, reaction with cinchona alkaloids and Selectfluor (J. Fluorine Chem. 2006, 127, 548). Using a catalytic amount of the alkaloid and a sodium acetate activator, they made α-fluoroketones with a C-F quaternary carbon from acyl enol ethers in up to 54% ee.

"The main reason for this low enantioselectivity is the high reactivity of Selectfluor to substrates," Shibata says. "While we overcame this by reducing the reactivity of the substrates, it was not enough." To increase the enantioselectivity, his group now is working on developing a new fluorinating reagent with a reactivity that's adjustable by the reaction conditions.

Another route to α-fluoroketones has been proposed by Masaharu Nakamura and colleagues at the University of Tokyo (Angew. Chem. Int. Ed. 2005, 44, 7248). Their approach converted a racemic α-fluoro-β-ketoester through enantioselective decarboxylation. Using a Pd catalyst and chiral phosphinooxazoline ligand, they could produce α-allyl-α-fluoroketones in as high as 96% yield and 99% ee.

While others have focused on α-fluorocarbonyls, Oxford's Gouverneur has synthesized structurally diverse fluoroorganic compounds through electrophilic fluorodesilylation of aryl-, allyl-, vinyl-, and allenylmethylsilanes (Org. Biomol. Chem. 2006, 4, 26). This area had largely been neglected, she believes, because early work had looked at less reactive aryl silanes. And she extended the method to enantioselective reactions.

Like Shibata, Gouverneur and coworkers used fluorinated cinchona alkaloids generated in situ with Selectfluor to prepare allylic fluorides with up to 96% enantioselectivity (Angew. Chem. Int. Ed. 2003, 42, 3291). Since then, fluorodesilylation with Selectfluor of acyclic homochiral allylsilanes has also yielded enantiopure β-fluorinated-α-substituted carboxylic acids with an allylic monofluorinated stereogenic center (Org. Lett. 2005, 7, 4495).

Simultaneously inserting a trifluoromethyl group and creating a chiral center under reagent control is even more challenging. "Enantioselective trifluoromethylation is very difficult to achieve," says Thierry Billard, associate researcher in the SERCOF Laboratory at Claude Bernard University, in Lyon, France, who with lab director Bernard R. Langlois has developed many trifluoromethylation reagents. "To my knowledge, there is no general enantioselective method to trifluoromethylate prochiral compounds.

"Incontestably, the best way presently to easily and efficiently obtain a chiral center bearing a CF₃ moiety remains the building-block approach-asymmetric reduction of, or nucleophilic addition to, a trifluoromethylcarbonyl group," Billard continues. As an example, he points to Bristol-Myers Squibb's HIV drug Sustiva, which is produced by the asymmetric addition of an organometallic compound onto a trifluoromethylcarbonylated substrate.

Nevertheless, good results have been obtained using chiral substrates and the trifluoromethylating reagent CF₃Si(CH₃)₃ , or TMS-CF₃. Commonly called Ruppert's reagent, it was first prepared by Ingo Ruppert and coworkers in 1984 at the Inorganic Chemistry Institute of the University of Bonn, in Germany; many now call it Ruppert-Prakash reagent, after G. K. Surya Prakash at the University of Southern California found its utility as a stable source of the nucleophilic trifluoromethyl anion. Since 1989, TMS-CF₃ has been widely used for the trifluoromethylation of carbonyl compounds and other substrates.

A drawback has been its synthesis, which typically uses the ozone-depleting substance CF₃Br. About three years ago, Tosoh developed a process to make the reagent in up to ton quantities at about one-fifth the price. "It had been very expensive, and people had tried experiments on the bench that they couldn't afford to scale up," Byron says. The company is one of the world's largest producers of HBr, he adds, and the reagent is produced in a contained system to avoid problems with the starting material.

Prakash; Olah; and former postdoc Jinbo Hu, now a research professor at Shanghai Institute of Organic Chemistry (SIOC), developed a process in 2003 to make TMS-CF₃ from trifluoromethane, a cheap starting material, and diphenyl disulfide (J. Org. Chem. 2003, 68, 4457). It turns out, Hu adds, that trifluoromethyl phenyl sulfone and sulfoxide intermediates in the process are themselves excellent nucleophilic trifluoromethylating agents. But the new process to make them and TMS-CF₃ hasn't been commercialized.

Before TMS-CF₃, trifluoromethylcopper chemistry had emerged, but it is usually limited to trifluoromethylating aryl and alkenyl iodides and bromides at high temperatures, Hu explains. Fluorosulfonyl difluoroacetate esters, developed by Qing-yun Chen at SIOC in the 1980s, are also a source of trifluoromethyl groups in the presence of copper catalysts; DuPont produces these esters from TFE. And Ying Chang and Chun Cai at Nanjing University of Technology, in China, have used sodium trifluoroacetate and copper halide catalysts to trifluoromethylate aldehydes (Tet. Lett. 2005, 46, 3161).

Since the late 1990s, a series of nucleophilic trifluoromethylation methods, employing fluoroform, fluoral, and trifluoroacetic and trifluoromethanesulfinic acid derivatives, as well as CF₃I and tetrakis(dimethylamino)ethylene (TDAE) have been developed. In 2001, the method of using TDAE and CF₃I came from Dolbier's lab at the University of Florida in an effort to develop a reagent that would be easy to use, he says.

It is comparable in utility with TMS-CF₃, which works somewhat better on enolizable substrates, and it been shown to work on a wide variety of substrates. Recently, Dolbier's group extended the chemistry to introduce other perfluoroalkyl groups (R_F), such as C₂F₅ or n-C₄F₉, by using R_FI and TDAE (J. Org. Chem. 2006, 71, 3564). "One of the problems right now is that TDAE is not commercially available," Dolbier says. His lab has been making research quantities while looking for a commercial manufacturer.

Many attempts at enantioselective trifluoromethylation have used existing CF₃ reagents in chiral, nonracemic form or in combination with a chiral fluoride source. Results from trifluoromethylating reagents, such as TMS-CF₃, with chiral fluorides or chiral Lewis bases have been interesting but limited, Billard comments, and dependent on the hindered structure of the substrate (J. Fluorine Chem. 2005, 126, 173).

Trifluoroacetamides (Angew. Chem. Int. Ed. 2003, 42, 3133) and trifluoromethanesulfinamides (Synlett. 2004, 2119) are strong contenders as trifluoromethylating reagents, he adds. Since the reagents themselves can be chiral, Billard and Langlois have considered them for enantioselective reactions but with disappointing results to date; the best trifluoromethylation of benzaldehyde gave just 31% yield and 30% ee (Chem. Eur. J. 2005, 11, 939).

Asymmetric electrophilic trifluoromethylation has progressed even less than nucleophilic approaches, Togni says. A decade ago, Teruo Umemoto and coworkers at Daikin prepared (trifluoromethyl)dibenzothiophenium salts, later studied by Cahard and Ma as well. As an alternative to these, Togni has proposed hypervalent iodine compounds based on cheap starting materials (Chem. Eur. J. 2006, 12, 2579).

"Similar iodine reagents existed before but only with perfluoroalkyl groups and not CF₃ because of problems with the synthesis," Togni says. His group overcame them by changing the sequence of the synthesis and introducing the CF₃ group at the very end. Having seen promising reactivities, he says, "we're now synthesizing optically active variants and looking for chiral catalysts for electrophilic trifluoromethylation."

Another approach to trifluoromethylation is radical chemistry. Rhodia developed, and has transferred to Shasun Pharma, a new radical trifluoromethylation technology derived from triflic acid chemistry. Based on trifluoromethanesulfonyl chloride to generate the CF₃ radical, it competes with classical halogen exchange to generate CF₃ groups in aliphatic compounds, explains Michel Spagnol, Shasun Pharma's vice president for sales and marketing.

In this process, such radical chemistry by its nature isn't enantioselective. But access to chiral building blocks is still possible, Spagnol points out, "because we can couple the radical trifluoromethylation chemistry with our hydrolytic kinetic resolution technology" for generating enantiomers.

Similarly, approaches for introducing difluoromethyl groups exist, based on older reagents such as SF₄, DAST, TBAF, and BrF₃, and on newer approaches. "Unlike TMS-CF₃ chemistry, TMS-CF₂H is not effective in the nucleophilic difluoromethylation of carbonyl compounds," Hu says. Prakash, Olah, and Hu did find, however, that difluoromethyl phenyl sulfone (PhSO₂CF₂H) is a good reagent for difluoromethylating structurally diverse carbonyl compounds (Eur. J. Org. Chem. 2005, 2218) and alkyl halides (Org. Lett. 2004, 6, 4315).

Hu and coworkers in China have continued work with the PhSO₂CF₂H reagent and synthesized chiral α-difluoromethyl amines from N-(tert-butanesulfinyl)imines (Angew. Chem. Int. Ed. 2005, 44, 5882). They also developed an improved nucleophilic difluoromethylation chemistry by using TMS-CF₂SO₂Ph and a milder, more environmentally benign desulfonylation step (Tet. Lett. 2005, 46, 8273).

Just recently, Shibata, Toru, and colleagues looked at Lewis acid-catalyzed tri- and difluoromethylation reactions of aldehydes (Chem. Commun., published online May 10, dx.doi.org/10.1039/b603041f). They used titanium or copper catalysts with TMS-CF₃ for trifluoromethylation and with TMS-CF₂SePh, TMS-SiCF₂SPh, and similar reagents for difluoromethylations. "We are now focusing on developing enantioselective reactions," Shibata says.

Overall, "nucleophilic trifluoromethylation and difluoromethylation have been tamed," Hu believes. "It is reasonable to say that these reactions are possible across a broad range of starting materials to yield many desired products."

The development of new fluorination reactions is expected to increase the availability of fluorine-containing structures and spark the interest of drug and agrochemical producers. As customers find it easier to explore having fluorine in their molecules, fine chemicals manufacturers hope demand for custom syntheses and building blocks will grow.

Change is happening already, suggests Andreas Meudt, global head of R&D for Clariant's pharmaceutical fine chemicals business. "We see an increasing interest, in general, in fluorine-containing molecules and in more and more 'exotic' functional groups that have not been used before."