Issue Date: February 25, 2013
Fluorine Chemistry Continues Apace
Fluorine chemists have been on a roll lately, generating a torrent of research papers reporting new tricks for incorporating fluorine into organic molecules. The field’s abundance of riches has come about in response to a call by pharmaceutical and agrochemical companies to generate new leads for drugs and pesticides.
The interest in fluorine stems from the ability of the small, highly electronegative element to increase the metabolic stability of molecules. It also improves their ability to penetrate the lipid bilayer membranes of cells—their lipophilicity—and hit their intended targets.
“There are a lot of good fluorine papers being published today,” says Harvard University’s Tobias Ritter, one of the researchers leading the fluorine vanguard. “The field is booming.”
“It’s hard to keep up with all the published work, even for those of us working in the field,” adds John F. Hartwig of the University of California, Berkeley. Hartwig is one of a handful of synthetic organic chemists who recently jumped into fluorine chemistry to help address pharmaceutical firm needs.
Drawing on methods developed for organic synthesis, the new fluorinations are typically safer, easier, greener, more effective, and less expensive than the traditional fluorination methods they are replacing.
Traditional fluorination reaction protocols often require specialized training to handle hazardous reagents. In addition, the harsh reagents and reaction conditions can obliterate functional groups already in place on a molecule. The traditional approaches also have not been very selective in adding fluorine or a fluorinated group at the desired location in a molecule, which is imperative for making drug and pesticide active ingredients.
One of the benefits of the new developments is that molecule designers now have the flexibility to prepare more fluorinated analogs in fewer reaction steps. Chemists usually start from scratch multiple times with simple prefluorinated reagents to make sets of complex fluorinated molecules for testing. They now have the option to prepare complex nonfluorinated intermediates first and then fine-tune them to make multiple fluorinated analogs by adding fluorine at various locations in the molecules.
Among some of the latest examples to build on this platform, two research groups have independently reported the first catalytic hydrotrifluoromethylations of terminal alkenes. In this reaction, hydrogen adds to one carbon and CF3 adds to the other carbon of a double bond. Although alkene hydroalkylations are established, the fluorinated version remains underdeveloped. Trifluoromethyl groups are key in molecules such as the HIV reverse transcriptase inhibitor efavirenz, the antidepressant fluoxetine, and the herbicide saflufenacil.
In one of the reports, Feng-Ling Qing and coworkers at Shanghai Institute of Organic Chemistry describe a silver-catalyzed method that uses the common trifluoromethylating reagent (CH3)3SiCF3 as the CF3 source and 1,4-cyclohexadiene as the H source (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201208971). In the second report, a team led by Véronique E. Gouverneur of Oxford University used a light-activated ruthenium bipyridine catalyst coupled with a trifluoromethyl diarylsulfonium salt as the CF3 source and methanol as the H source (J. Am. Chem. Soc., DOI: 10.1021/ja401022x).
Both approaches proceed via a radical intermediate under mild conditions and work with cyclic or linear substrates without disturbing ester, alcohol, amine, or other functional groups already on the molecules. The methods also work to functionalize alkynes.
Another fluorination target is the trifluoromethylthio group, SCF3. This functional group is one of the most lipophilic substituents available to chemists. It’s found in commercial products such as the appetite suppressant tiflorex and the insecticide vaniliprole. Chemists typically incorporate SCF3 into molecules indirectly by exchanging fluorine with another halogen, adding CF3 to a sulfur-containing compound, or adding sulfur and CF3 to a compound. But chemists would prefer to directly add an SCF3 group when and where they need it.
To that end, several research teams have reported new approaches for trifluoromethylthiolation. In one of the latest examples, Long Lu and Qilong Shen of Shanghai Institute of Organic Chemistry and their coworkers developed a new SCF3-containing hypervalent iodine reagent. Hypervalent iodine compounds make up a versatile class of fluorinating reagents. The researchers used the reagent to transfer SCF3 to a variety of β-ketoesters, aryl and vinyl boronic acids, amides, alkynes, and other compounds (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201209817).
In yet another new fluorination, Alexander D. Dilman and coworkers at the N. D. Zelinsky Institute of Organic Chemistry, in Moscow, have reported an approach for synthesizing compounds containing difluoromethyl groups (Org. Lett., DOI: 10.1021/ol400122k). Like other types of fluorinations, introducing CF2 into a molecule once required either a harsh fluorinating reagent to functionalize a carbonyl group or a multistep building-block synthesis.
Dilman’s team instead opted to use (CH3)3SiCF2Br as a difluorocarbene source to insert CF2 into the C–Zn bond of organozinc bromide compounds. Adding iodine completes the reaction to form a terminal CF2I group. Iodine in the product could be beneficial for providing a reaction site for further chemistry, such as cross-coupling to form more complex molecules.
For Harvard’s Ritter, his group’s most recent paper focuses on using an efficient difluoroimidazole reagent it invented, now a commercial product called PhenoFluor, to carry out the deoxyfluorination of alcohols (J. Am. Chem. Soc., DOI: 10.1021/ja3125405). In this reaction, F replaces an OH group. The reaction, which works for simple and structurally complex alcohols, may be useful for quickly adding the 18F radioisotope to molecules for positron emission tomography (PET) medical imaging.
One of the latest fluorine papers from Hartwig’s group at UC Berkeley reports the synthesis of aryl difluoromethyl ethers from phenols (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201209250). The OCF2H group is increasingly being incorporated into drugs and agrochemicals, such as pantoprazole used to treat gastric acid reflux. The new twist unveiled in Hartwig’s paper is using a solution of readily available difluoromethyltriflate as the fluorine source, rather than the ozone-depleting gas chlorodifluoromethane (Freon 22) typically used.
Despite the great strides being made in fluorinations, “big challenges still remain,” Ritter says. For example, the parent transformation of making C–F bonds is still not practical and is less developed than other fluorinations, such as trifluoromethylation, he says.
Fluorine researchers agree it’s difficult to do justice and acknowledge all of the high-quality research papers coming out today. “But one thing is clear,” Hartwig observes: “A lexicon of methods to incorporate fluorine into organic molecules under mild conditions is being developed.”
- Chemical & Engineering News
- ISSN 0009-2347
- Copyright © American Chemical Society