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Synthesis of Aromatic Trifluoromethyl Compounds: the Potential for Large Scale Application

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Synthesis of Aromatic Trifluoromethyl Compounds: the Potential for Large Scale Application FUORINE CHEMISTRY HEINZ STEINER Solvias AG, Römerpark 2, 4303 Kaiseraugst, Switzerland Heinz Steiner Synthesis of aromatic trifluoromethyl compounds: The potential for large scale application KEYWORDS: trifluoromethylation, trifluoromethylating reagents, trifluoromethyl aromatics, deoxofluorination. This article provides an overview on reagents and protocols for the synthesis of aromatic trifluoromethyl Abstract compounds. The generation of trifluoromethylated aromatic building blocks, the deoxoflurination of carboxylic acids, and the trifluoromethylation of aromatic precursors are covered by this review. Issues that favor or hinder the large scale application of particular reagents and protocols are presented. Remarkably, only one out of more than 10 protocols covered by this review is currently applied on large production scale, a few others have been applied on a 5 kg to 100 kg scale. INTRODUCTION THE TERM “POTENTIAL FOR LARGE SCALE APPLICATION” (2) Trifluoromethylated aromatic rings are common motifs in When discussing the terms ‘potential for large scale pharmaceutical and agrochemical active compounds as application’ or ‘viability for industrial application’ aspects well as in performance materials (1). For many decades, such as cost of goods, processing cost, hazard potential, or formation of aryl-CF3 compounds has been limited to a few process safety are of increasing importance. Similar aspects traditional technologies, especially the perchlorination of are also discussed with respect to “green chemistry”. aromatic methyl-groups followed by exhaustive chlorine- fluorine exchange using anhydrous HF (AHF) or SbF5, or the In the current article the ‘potential for large scale application’ deoxofluorination of carboxylic acids using sulfur tetrafluoride. will be qualitatively assessed, regarding: In recent years, a plethora of new reagents and protocols - cost of starting materials, reagents, solvents, catalysts, have been developed at various universities, resulting in a auxiliaries tremendously expanded synthetic toolkit for R&D chemists. - chemoselectivity, regioselectivity, yield Whereas traditional methodologies are restricted to rather - processing cost basic compounds, modern protocols typically allow for late- - waste-generation stage introduction of the trifluoromethyl substituent into quite - practicability of process, e.g. complexity of reagent complex molecules. It’s conceivable that these opportunities handling, need for containment. will significantly increase the number of trifluoromethylated aromatic molecules in the development pipelines of the industry. Therefore, the need for industrially viable REAGENTS FOR THE SYNTHESIS OF TRIFLUOROMETHYLATED trifluoromethylation processes increases. The aim of this article AROMATIC COMPOUNDS is to highlight the most important issues and cost drivers in the generation of aromatic trifluoromethyl compounds. Based on Scheme 1 depicts typical routes pertaining to the selection of the introduction into common reagents and protocols used important reagents that can be used for the synthesis of for the generation of aryl-CF3 compounds, the advantages trifluoromethylated aromatic compounds. and disadvantages of a series of protocols are presented. Formation of heteroaromatic CF3-compounds by cyclisation Whereas natural fluoride sources such as CaF2, KF, and NaF using building blocks such as trifluoroacetic acid is outside the cannot be used as primary fluorine-sources for the synthesis of scope of the present article. trifluoromethylated aromatic compounds, HF, SF4 and Ar-SF3 26 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 selective late-stage trifluoromethylation based on an expensive reagent is more cost-efficient than a 10-step route including the use of a trifluormethylated early intermediate. In the following, the reagents depicted in Scheme 1 are briefly characterized. Prices given are typically based on current Scifinder®-prices. Retail prices of various trifluoromethylating reagents have been previously reviewed (3). 1st Level Reagents Anhydrous Hydrogen Fluoride (AHF)(4) Hydrogen fluoride is produced by treatment of calcium fluoride with concentrated sulfuric acid. Anhydrous hydrogen fluoride (AHF) is used in industry in annual amounts of > 1’000’000 tonnes, e.g. for the production of fluoropolymers or as fluorination agent. Hydrogen fluoride is an acute poison that immediately and permanently damages lungs and eyes. In addition it is a systemic poison since it interferes with the calcium metabolism. Only a few manufacturers are able to work with AHF because of its extremely hazardous properties. AHF (bp: 19.5°C) can only Scheme 1. Routes to reagents for the synthesis of trifluoromethylated aromatic compounds. be used in strictly closed apparatus (autoclaves) installed in a secondary containment. HF-monitoring and the highest level of personnel (“1st level reagents”) are suitable reagents to convert protection has to be ensured. In addition, HF emission to the environment has to be prevented by highly efficient functional groups, i.e. CCl3 groups or carboxylic acids into the scrubbers. AHF is the cheapest and most important CF3- group. Fluoroform, trifluoroacetates (sodium-, fluorination reagent for industrial application. In April 2012 the postassium-, methyl-), CClF2COOMe, and trifluoromethylsulfonyl chloride (“2nd level reagents”) are price for AHF was USD 1250 / ton resulting in a cost of < USD 1 / amongst the most simple and therefore cost-effective mol aryl-CF3 (5). trifluoromethylating reagents. Further transformation results in rd a broad range of 3 level trifluoromethylating reagents, such Sulfur Tetrafluoride (SF4) (6) as trifluoromethyl iodide, trifluoromethyl trimethylsilane, SF4 has been used as a deoxofluorination reagent for more trifluoromethylphenyl ketone, or potassium than 50 years. Furthermore, it serves as a starting material trifluoromethylsulfonate. Trifluoromethyltrimethylsilane have been for the preparation of DAST, DeoxofluorTM, or XtalFluorTM , used to generate even more elaborated trifluoromethylating reagents that selectively transform carboxylic acids into reagents (“4th level reagents”) such as TrifluoromethylatorTM, acid fluorides without formation of trifluoromethyl trifluoromethyl tris-triphenylphosphine copper, compounds. Sulfur tetrafluoride (bp: -82°C) is a highly potassium(trifluoromethyl) trimethylborate, or the electrophilic reactive, toxic and corrosive gas which liberates AHF and trifluoromethylating reagents of Togni and Umemoto. thionylfluoride upon exposure to moisture. Because of its extremely hazardous properties SF4 can only be handled in Regarding reagent cost the following general conclusion can strictly closed apparatus (autoclaves) installed in a be drawn: The more elaborated, the higher the cost of a secondary containment. HF-monitoring and utmost protection of the operators has to be ensured. In addition, reagent per mol of CF3 compound, i.e. a particular reagent cannot be better priced than its precursor. scrubbers have to be in place to prevent emissions of any SF4 and AHF to the environment. Of course, such measures However, the cost impact of a particular trifluoromethylation result in increased processing costs. However, since raw protocol per mole of trifluoromethylated intermediate doesn’t materials (e.g. S, Cl2, NaF) are inexpensive, SF4 has great solely depend on the trifluoromethylating reagent, but also on potential as an economic fluorination reagent. other cost-drivers, e.g. the cost of the substrate and other raw Unfortunately, SF4 cannot be easily obtained in ton materials, the cost for waste, and the yield of the purified quantities because of regulatory transport restrictions. The trifluoromethyl compound. The potential of a particular only viable concept for the industrial use of SF4 requires reagent for a particular application can only be rated by an “on-site” production. Several protocols for the synthesis of in-depth analysis. For example, the cost of goods sold of a SF4 have been established, e.g. the chlorination of sulfur trifluoromethylated intermediate can be lower when using an followed by chlorine-fluorine exchange (7). Apart from expensive trifluoromethylation reagent but a cost-effective direct synthesis, SF4 is obtained as a byproduct from the process compared to a low-priced trifluoromethylation production of SF6, which is produced in > 10’000 tons a year reagent but an expensive process. Also, the most important and used as a dielectric medium in the electric industry (8). criterion is the cost of goods sold of the final active substance. 100 kg quantities of SF4 are currently available for about It might happen that a 8-step synthesis route including a USD 200/kg. Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 27 rd Arylsulfurtrifluoride (Ar-SF3) (9) 3 Level Reagents Recently, arylsulfurtrifluorides were established as Trifluoromethyl bromide (CF3Br)(13) deoxofluorination reagents, e.g. 2,6-dimethyl-4-tert.- Trifluoromethyl bromide, also known as Halon 1301, has been butylphenyl sulfurtrifluo ride (Fluolead®), a crystalline solid (mp: used for as a fire protecting and refrigeration agent on very 66-67°C) or PhSF3 a liquid (bp: 70°C at 10 mm Hg). large scale, but also for trifluoromethylation reactions and for Phenylsulfurtrifluoride is extremely moisture sensitive whereas the synthesis of trifluoromethyling reagents. The Montreal ® Fluolead only gradually reacts with moisture or water to form Protocol requires that all production of new CF3Br be ceased
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