SCIENCE & TECHNOLOGY
FLUORINE CHEMISTRY CONTINUES APACE Researchers stay on a HOT STREAK creating simpler and more efficient reactions for making drugs and pesticides STEPHEN K. RITTER, C&EN WASHINGTON
FLUORINE CHEMISTS have been on a
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).
imperative for making drug and pesticide roll lately, generating a torrent of research active ingredients. papers reporting new tricks for incorporatOne of the benefits of the new developing fluorine into organic molecules. The ments is that molecule designers now have field’s abundance of riches has come about the flexibility to prepare more fluorinated in response to a call by pharmaceutical and analogs in fewer reaction steps. Chemists agrochemical companies to generate new usually start from scratch multiple times leads for drugs and pesticides. with simple prefluorinated reagents to The interest in fluorine stems from the make sets of complex fluorinated molecules ability of the small, highly electronegative for testing. They now have the option to BOTH APPROACHES proceed via a radielement to increase the metabolic stability prepare complex nonfluorinated intermecal intermediate under mild conditions of molecules. It also improves their ability diates first and then fine-tune them to make and work with cyclic or linear substrates to penetrate the lipid bilayer membranes multiple fluorinated analogs by adding fluowithout disturbing ester, alcohol, amine, of cells—their lipophilicity—and hit their rine at various locations in the molecules. or other functional groups already on the intended targets. Among some of the latest examples to molecules. The methods also work to func“There are a lot of good fluorine papers build on this platform, two research groups tionalize alkynes. being published today,” says Harvard Unihave independently reported the first cataAnother fluorination target is the triversity’s Tobias Ritter, one of the researchlytic hydrotrifluoromethylations of termifluoromethylthio group, SCF3. This funcers leading the fluorine vanguard. “The nal alkenes. In this reaction, hydrogen adds tional group is one of the most lipophilic field is booming.” to one carbon and CF3 adds to the other substituents available to chemists. It’s found “It’s hard to keep up with all the pubcarbon of a double bond. Although alkene in commercial products such as the appetite lished work, even for those of us suppressant tiflorex and the insecworking in the field,” adds John F. ticide vaniliprole. Chemists typicalFLUORINE FRENZY Many new fluorination reactions Hartwig of the University of Calily incorporate SCF3 into molecules are flooding the chemical literature. fornia, Berkeley. Hartwig is one indirectly by exchanging fluorine of a handful of synthetic organic with another halogen, adding CF3 Hydrotrifluoromethylations chemists who recently jumped to a sulfur-containing compound, Ru catalyst AgNO3 into fluorine chemistry to help ador adding sulfur and CF3 to a comlight PhI(OAc)2 + H H RSCF3 (CH3)3SiCF3 dress pharmaceutical firm needs. pound. But chemists would prefer Cyclohexadiene methanol CF3 CF3 R R R Drawing on methods develto directly add an SCF3 group when oped for organic synthesis, the and where they need it. Trifluoromethylthiolations new fluorinations are typically To that end, several research F3CS I O safer, easier, greener, more effecteams have reported new aptive, and less expensive than the proaches for trifluoromethylthiolaSCF3 B(OH)2 traditional fluorination methods tion. In one of the latest examples, they are replacing. Long Lu and Qilong Shen of ShangR R Traditional fluorination rehai Institute of Organic Chemistry action protocols often require and their coworkers developed a Difluoromethylations specialized training to handle new SCF3-containing hypervalent BrF2CSi(CH3)3 I2 hazardous reagents. In addition, iodine reagent. Hypervalent iodine R ZnBr R CF2I the harsh reagents and reaction compounds make up a versatile conditions can obliterate funcclass of fluorinating reagents. Deoxyfluorinations tional groups already in place on The researchers used the reagent R N N R OH F a molecule. The traditional apto transfer SCF3 to a variety of F F proaches also have not been very β-ketoesters, aryl and vinyl boronic R R R R R R selective in adding fluorine or a acids, amides, alkynes, and other R = various groups, Ph = phenyl, Ac = acetyl fluorinated group at the desired compounds (Angew. Chem. Int. Ed., location in a molecule, which is DOI: 10.1002/anie.201209817). WWW.CEN-ONLINE.ORG
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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 crosscoupling 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.
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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.” ◾
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