26 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015KEYWORDS: trifluoromethylation, trifluoromethylating reagents, trifluoromethyl aromatics, deoxofluorination.Abstract This article provides an overview on reagents and protocols for the synthesis of aromatic trifluoromethyl 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. Synthesis of aromatic trifluoromethyl compounds: The potential for large scale applicationINTRODUCTIONTrifluoromethylated aromatic rings are common motifs in pharmaceutical and agrochemical active compounds as well as in performance materials (1). For many decades, formation of aryl-CF3 compounds has been limited to a few traditional technologies, especially the perchlorination of aromatic methyl-groups followed by exhaustive chlorine-fluorine exchange using anhydrous HF (AHF) or SbF5, or the deoxofluorination of carboxylic acids using sulfur tetrafluoride. In recent years, a plethora of new reagents and protocols have been developed at various universities, resulting in a tremendously expanded synthetic toolkit for R&D chemists. Whereas traditional methodologies are restricted to rather basic compounds, modern protocols typically allow for late-stage introduction of the trifluoromethyl substituent into quite complex molecules. Its conceivable that these opportunities will significantly increase the number of trifluoromethylated aromatic molecules in the development pipelines of the industry. Therefore, the need for industrially viable trifluoromethylation processes increases. The aim of this article is to highlight the most important issues and cost drivers in the generation of aromatic trifluoromethyl compounds. Based on the introduction into common reagents and protocols used for the generation of aryl-CF3 compounds, the advantages and disadvantages of a series of protocols are presented. Formation of heteroaromatic CF3-compounds by cyclisation using building blocks such as trifluoroacetic acid is outside the scope of the present article.THE TERM POTENTIAL FOR LARGE SCALEAPPLICATION (2)When discussing the terms potential for large scale application or viability for industrial application aspects such as cost of goods, processing cost, hazard potential, or process safety are of increasing importance. Similar aspects are also discussed with respect to green chemistry.In the current article the potential for large scale application will be qualitatively assessed, regarding:- cost of starting materials, reagents, solvents, catalysts, auxiliaries- chemoselectivity, regioselectivity, yield- processing cost- waste-generation - practicability of process, e.g. complexity of reagent handling, need for containment.REAGENTS FOR THE SYNTHESIS OF TRIFLUOROMETHYLATED AROMATIC COMPOUNDS Scheme 1 depicts typical routes pertaining to the selection of important reagents that can be used for the synthesis of trifluoromethylated aromatic compounds. Whereas natural fluoride sources such as CaF2, KF, and NaF cannot be used as primary fluorine-sources for the synthesis of trifluoromethylated aromatic compounds, HF, SF4 and Ar-SF3 FUORINE CHEMISTRYHEINZ STEINERSolvias AG, Rmerpark 2, 4303 Kaiseraugst, Switzerland27 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015selective 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). 1stLevel 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 > 1000000 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: 19.5C) can only be used in strictly closed apparatus (autoclaves) installed in a secondary containment. HF-monitoring and the highest level of personnel protection has to be ensured. In addition, HF emission to the environment has to be prevented by highly efficient scrubbers. AHF is the cheapest and most important fluorination reagent for industrial application. In April 2012 the price for AHF was USD 1250 / ton resulting in a cost of < USD 1 / mol aryl-CF3 (5).Sulfur Tetrafluoride (SF4) (6) SF4 has been used as a deoxofluorination reagent for more than 50 years. Furthermore, it serves as a starting material for the preparation of DAST, DeoxofluorTM, or XtalFluorTM , reagents that selectively transform carboxylic acids into acid fluorides without formation of trifluoromethyl compounds. Sulfur tetrafluoride (bp: -82C) is a highly reactive, toxic and corrosive gas which liberates AHF and thionylfluoride upon exposure to moisture. Because of its extremely hazardous properties SF4 can only be handled in strictly closed apparatus (autoclaves) installed in a secondary containment. HF-monitoring and utmost protection of the operators has to be ensured. In addition, scrubbers have to be in place to prevent emissions of any SF4 and AHF to the environment. Of course, such measures result in increased processing costs. However, since raw materials (e.g. S, Cl2, NaF) are inexpensive, SF4 has great potential as an economic fluorination reagent. Unfortunately, SF4 cannot be easily obtained in ton quantities because of regulatory transport restrictions. The only viable concept for the industrial use of SF4 requires on-site production. Several protocols for the synthesis of SF4 have been established, e.g. the chlorination of sulfur followed by chlorine-fluorine exchange (7). Apart from direct synthesis, SF4 is obtained as a byproduct from the production of SF6, which is produced in > 10000 tons a year and used as a dielectric medium in the electric industry (8). 100 kg quantities of SF4 are currently available for about USD 200/kg.(1st level reagents) are suitable reagents to convert functional groups, i.e. CCl3 groups or carboxylic acids into the CF3- group. Fluoroform, trifluoroacetates (sodium-, postassium-, methyl-), CClF2COOMe, and trifluoromethylsulfonyl chloride (2nd level reagents) are amongst the most simple and therefore cost-effective trifluoromethylating reagents. Further transformation results in a broad range of 3rd level trifluoromethylating reagents, such as trifluoromethyl iodide, trifluoromethyl trimethylsilane, trifluoromethylphenyl ketone, or potassium trifluoromethylsulfonate. Trifluoromethyltrimethylsilane have been used to generate even more elaborated trifluoromethylating reagents (4th level reagents) such as TrifluoromethylatorTM, trifluoromethyl tris-triphenylphosphine copper, potassium(trifluoromethyl)trimethylborate, or the electrophilic trifluoromethylating reagents of Togni and Umemoto.Regarding reagent cost the following general conclusion can be drawn: The more elaborated, the higher the cost of a reagent per mol of CF3 compound, i.e. a particular reagent cannot be better priced than its precursor. However, the cost impact of a particular trifluoromethylation protocol per mole of trifluoromethylated intermediate doesnt solely depend on the trifluoromethylating reagent, but also on other cost-drivers, e.g. the cost of the substrate and other raw materials, the cost for waste, and the yield of the purified trifluoromethyl compound. The potential of a particular reagent for a particular application can only be rated by an in-depth analysis. For example, the cost of goods sold of a trifluoromethylated intermediate can be lower when using an expensive trifluoromethylation reagent but a cost-effective process compared to a low-priced trifluoromethylation reagent but an expensive process. Also, the most important criterion is the cost of goods sold of the final active substance. It might happen that a 8-step synthesis route including a Scheme 1. Routes to reagents for the synthesis of trifluoromethylated aromatic compounds. 3rd Level Reagents Trifluoromethyl bromide (CF3Br)(13) Trifluoromethyl bromide, also known as Halon 1301, has been used for as a fire protecting and refrigeration agent on very large scale, but also for trifluoromethylation reactions and for the synthesis of trifluoromethyling reagents. The Montreal Protocol requires that all production of new CF3Br be ceased by January 1, 1994. Recycled Halon 1301 and inventories produced before 1994 are now the only legal sources of supply. Because of the Montreal Protocol, the viability of CF3Br for industrial application is limited to critical uses which will continue, i.e. uses that can claim to be connected with national security (14). Trifluoromethyl iodide (CF3I)(15) Trifluoromethyl iodide has been tested as an alternative to CBrF3 as a fire-suppressing agent. It is frequently utilized for aromatic trifluoromethylation in R&D. CF3I (bp: -21C) is not corrosive and can be handled in normal autoclaves. It is probably carcinogenic to humans but not acute toxic.In contrast to Halon 1301, CF3I is not covered by the Montreal Protocol. 5 kg quantities of CF3I are currently available for about USD 2000/kg. CF3I can be prepared by several processes, e.g. the reaction of fluoroform with iodide and oxygen.A 1:1 adduct of trifluoromethyliodide with tetrammethylguainidine (CF3I-TMG) was recently disclosed as an easy to handle liquid trifluoromethylating reagent.A 30g batch of the reagent stored at 0C showed no sign of decomposition over two months (16). Trifluoromethyltrimethylsilane (Me3SiCF3 ,TMSCF3) / Trifluormethyltriethylsilane (Et3SiCF3 , TESCF3)(17) TMSCF3 (Ruppert-Prakash reagent) is a stable and easy to handle liquid trifluoromethylation reagent (bp: 55C) which has extensively been used in R&D for three decades. It can be handled without special equipment or safety precautions. For R&D applications TESCF3 is often preferred because its higher boiling point (56-57C at 60 mbar) allows higher reaction temperatures.Whereas the original Ruppert preparation protocol of TMSCF3 is based on CF3Br (17a), Prakash et al (10b) were able to react fluoroform with Me3SiCl at -85C using potassium hexamethyldisilazane (KHMDS) as a base. From a raw material point of view, this is a very economical process, since fluoroform is a large volume byproduct in the synthesis of polytetrafluoroethylene and trimethylchlorosilane is inexpensive. The most expensive raw material in this synthesis is KHMDS. From a process point of view, the very low temperature (-85C) seems to be an obstacle. The same protocol is also well suited for the synthesis of TESCF3. The current price of TMSCF3 is about USD 3000/5 kg. Metal trifluoromethanesulfinates (CF3SO2Na, CF3SO2K, (CF3SO2)2Zn) (18, 19) CF3SO2Na (Langlois reagent), CF3SO2K and (CF3SO2)2Zn (a Baran reagent) are solid salts which can easily be prepared from CF3SO2Cl and handled in air in standard laboratory equipment without any special precaution. In combination with tert.-butyl hydroperoxide (TBHP) they have been used as radical trifluoromethylating reagents. These reagents are currently commercially available in 5 g to 100 g portions. Arylsulfurtrifluoride (Ar-SF3) (9) Recently, arylsulfurtrifluorides were established as deoxofluorination reagents, e.g. 2,6-dimethyl-4-tert.-butylphenyl sulfurtrifluo ride (Fluolead), a crystalline solid (mp: 66-67C) or PhSF3a liquid (bp: 70C at 10 mm Hg). Phenylsulfurtrifluoride is extremely moisture sensitive whereas Fluolead only gradually reacts with moisture or water to form HF. Ar-SF3 compounds can be generated by reaction of diaryldisulfides with chlorine or bromine and potassium fluoride. In the deoxofluorination of carboxylic acids two equivalents of ArSOF are generated. ArSOF recycling might be a prerequisite for a large scale application of Ar-SF3. Currently, Fluolead is only commercially available in 100 g quantities. 2nd Level Reagents Fluoroform (CHF3) (10) Fluoroform can be prepared by chlorine-fluorine exchange of trichloromethane. However, about 20000 tons each year are produced as byproduct in the industrial manufacturing of fluoro polymers. In research, fluoroform is used as a trifluoromethylation reagent and as starting material for the preparation of 3rd level trifluoromethylating reagents. Fluoroform is a non-toxic, ozone-friendly gas (bp: -82C). It has a warming potential of >104 compared to CO2 and a >240-year atmospheric lifetime. Fluoroform is highly attractive as a CF3 source from the perspective of availability and cost, and also of ecology, safety, and atom-economy. Fluoroform is currently available for about USD 600/1 kg.Sodium trifluoroacetate, Potassium trifluoroacetate, Methyl trifluoroacetate, Methyl chlorodifluoroacetate (11) Alkaline trifluoroacetates have been described as useful reagents for trifluoromethylation by thermal decarboxylation in the presence of CuI. Sodium trifluoroacetate and potassium trifluoroacetate are toxic and very hygroscopic solids and thus difficult to handle. Methyltrifluoroacetate (MTFA) requires high reaction temperatures (140-180C) for the decarboxylative trifluoromethylation reaction. Because of the low boiling point of MTFA (43C) such reactions have to be performed in autoclaves. These reagents benefit from the fact, that the precursor trifluoroacetic acid (TFA) is produced in large scale. TFA itself is widely used in organic chemistry, but it hasnt been applied as a trifluoromethylating reagent so far. MTFA is currently available in multi-kg amounts for about USD 60/kg, the current retail price of 1 kg TFA-Na is about USD 300. Apart from MTFA also methyl chlorodifluoroacetate (MCDFA) can be used for this type of decarboxylative chemistry. Its advantages compared to MTFA are the lower vapor pressure (bp: 79-81C) and the lower decarboxylation temperatures (80-120C). MCDFA is a byproduct in the synthesis of TFA, its current retail price of 1 kg is approx. USD 500.Trifluoromethanesulfonylchloride (Triflic chloride; CF3SO2Cl)(12) CF3SO2Cl is a difficult to handle liquid because it is very corrosive, low-boiling (bp: 30C) and it easily hydrolyses on air. It can be synthesized by electro fluorination of methane sulfonic acid of trifluoromethyl sulfonic acid (triflic acid) followed by chlorination. Triflic chloride is not yet produced as bulk chemical. However, based on the low retail price of triflic acid (USD 100/1.7 kg), it certainly has the potential for a reasonably priced bulk trifluoromethylating reagent.28 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015examined. Variation of the boron substituent(e.g. benzyloxy or 2-methoxyethyl) resulted in reagents with similar reactivity but improved thermal stability, i.e. the tris-benzyloxy derivative decomposes at temperatures > 170C. This reagent is currently commercially available in gram quantities.Electrophilic trifluoromethylating reagents (26) In 1984, Yagupolskii and co-workers (27) successfully achieved electrophilic trifluoromethylation by means of diaryl(trifluoromethyl)sulfonium salts such as 147531-11-1. Since then, additional so-called shelf-stable electrophilic trifluoromethylating reagents have been developed and used in academic and industrial research. Figure 1 shows a selection of such reagents.For example the Togni reagents can be exposed to moist air for short periods of time without any apparent alteration. Investigations of the thermal stability of Tognis reagents I and II by Novasep Synthesis (28) indicated that some samples of Tognis reagent II are impact-sensitive. The Togni group concluded that the reagents are not explosive under typical laboratory and reaction conditions and that these reagents do not require severe safety measures (29). It is interesting to note that Tognis reagent II is sold by retailers as a mixture with diatomaceous earth in order to reduce explosibility.The reagents depicted in Figure 1 are commercially available in portions up to 100 g.Methyl fluorosulphonyldifluoroacetate (20) Methyl fluorosulphonyldifluoroacetate was introduced in 1989 by Chen and Wu as a new trifluoromethylating reagent. It is a easy to handle liquid with a boiling point of 118C. This reagent can be prepared from chloroform, HF and SO3. It is currently available for about USD 1000/1 kg. 2,2,2-Trifuoroacetophenone (21)Aryl-trifuoromethylketones such as 2,2,2-Trifuoroacetophenone have been described as an excellent trifuoromethyl source. 2,2,2-Trifuoroacetophenone is a liquid (bp: 153C) that can be easily synthesized from bulk precursors, such as fuoroform and bromobenzene. Therefore this is a potential low- to medium-cost trifuoromethylating reagent for large scale application. It is currently available for about USD 1000/1 kg.Phenyltrifuoromethylsulphone (22) Phenyltrifuoromethylsulphone is a liquid (bp: 203-205C) that can be easily synthesized from bulk precursors, such as sodium trifuoroacetate and benzenesulfonic chloride. Therefore this is a potential medium-cost trifuoromethylating reagent for large application. It is currently available for about USD 3000/1 kg.4th Level ReagentsTrifluoromethylatorTM ((Phen)Cu-CF3) (23) (Phen)Cu-CF3 is a convenientto handle, thermally stable, single-component reagent for the trifluoromethylation of aryl iodides introduced by the Hartwig-group. It can be synthesized by the reaction of [CuOtBu]4 with 1,10-phenanthroline, followed byreaction with TMSCF3. Currently TrifluoromethylatorTM is commercially available in portions up to 100 g.Trifuoromethyl-tris(triphenylphoshino)copper[(Ph3P)3Cu(CF3)] andPhenanthroline-trifuoromethyltris(triphenylphosphine)copper [(phen)Cu(PPh)3(CF3)](24) [(Ph3P)3Cu(CF3)] and [(phen)Cu(PPh)3(CF3)] have been prepared in multi-gram scale from CuF2, PPh3 and TMSCF3 in high yield. [(Ph3P)3Cu(CF3)] is oxygen- and moisture-sensitive in solution, but it can be stored and handled in air for at least a month without decomposition. Currently these reagents are commercially available in 5 g quantities. Potassium (trifuoromethyl)trimethoxyborate (K[B(OMe)3CF3])(25) Recently potassium (trifluoromethyl)trimethoxyborate was introduced by the Goossen-group as an easy to handle CF3 source. [B(OMe)3CF3]K is generated in quantitative yields by stirring a mixture of TMSCF3, B(OH)3, and KF in anhydrous THF for one to two days. The crystalline, air-stable salt melts and decomposes at 116-118C. Solution in polar organic solvents such as DMF, start decomposing at approx. 80C. Accordingly, process safety both for the preparation and the application of this reagent has to be carefully Figure 1. Common reagents for electrophilic trifluoromethylation. Scheme 2. Typical protocols for the preparation of trifluoromethylated aromatic compounds. Phen* = 1,10-phenanthroline.29 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015IN ATTESA DELLA SIEGFRIED5th Anniversary Conference onFrontiers in Organic SynthesisTechnology FROST5For more information on membership contact the Flow Chemistry Societywww.owchemistrysociety.comBOOK YOUR EXHIBITION PLACE!Manufacturers are invited to present their outstanding equipment. The Flow Chemistry University section provides a great opportunity to demonstrate your product in a laboratory!FROST POSTER AWARD PROGRAMFROST5 will feature a POSTER AWARD PROGRAM FOR YOUNG SCIENTISTS (under age 35).Priority will be given for poster proposals which communicate innovative ideas to the conference audience. The aim of this posteraward program is to encourage and recognize young scientists with outstanding results. The winner will be announced during theGala Dinner on 22 October, 2015 and will be provided with a 20 minutes oral presentation slot on the last day of the conference, furthermore the 1st and 2nd best poster presentation will receive a feature paper slot to publish free of charge with Swiss Journal Molecules in the related special issue Guest Edited by Dr. Kerry Gilmore. For more information please visit at www.frostconferences.com or e-mail to frost@akcongress.com. We sincerely hope to see you in Budapest!CONFIRMED SPEAKERS OF FROST5FLOW CHEMISTRY ONNOVEL ROADS FROST5 aims to target innovative areas of ow chemistry with great potential for future.MAIN TOPICSLatest trends in ow-based organic chemistryLatest trends in industrial ow chemistryand End-to-End approachFlow chemistry for nanoatechnology and catalysisFlow chemistry in fracking and innon-conventional oil & gas productionGreen chemistry: ow approaches in environmental management and cleaning and cleaningwww.akcongress.comOctober 21-23, 2015 Budapest HungaryC. Oliver KappeUniversity of GrazPaul WattsNelson MandelaMetropolitan UniversityHolger LweJohannes Gutenberg UniversityRigoberto AdvinculaCase Western Reserve University Rafael LuqueUniversidad de CordobaVolker HesselTechnische Universiteit Eindhoven Alessandro MassiUniversity of Ferrara Mimi HiiImperial College LondonThomas WirthCardiff University Philip MillerImperial College LondonMike HawesSyrrisKerry GilmoreMax Planck InstituteWalter LeitnerRWTH Aachen Renzo LuisiUniversity of Baricompanies available that offer process R&D and production of up to multi-tonne amounts of trifluoromethylated aromatic compounds by deoxofluorination using SF4.Recently, 2,6-dimethyl-4-tert.-butylphenylsulfurtrifluoride (Fluolead) was introduced as a potential, less hazardous substitute for SF4 (34). Two equivalents of arenesulfinylfluoride result as a by-product that has to be separated from the benzotrifluoride product. If the by-product can be recycled, such a method could have some potential for large scale application. However, scope and limitations of this transformation have not been examined so far.Preparation of Aromatic Trifluoromethyl Compounds by Trifluoromethylation (1)IntroductionSeveral strategies have been pursued for the introduction of the trifluoromethyl group into aryl residues. Baran divided them into two general categories: those that functionalize the inherently reactive position of the substrate (innate trifluoromethylation) and those that utilize substrate prefunctionalization or a directing group (programmed trifluoromethylation) (35). Most often, the substitution of a functional group respectively the coupling of an aryl electrophile has been effected by the CuCF3 species, originally identified by McLoughlin and Thrower (36) and further developed by Kobayashi et al. (37). Scheme 4 gives an overview of the most important aromatic trifluoromethylation concepts, including nucleophilic, radical and electrophilic mechanism. Nucleophilic reagents work best with electron-deficient arenes while electrophilic and radical CF3 species are more suitable for electron-rich arenes such as amines and phenols. Whereas programmed trifluoromethylation is highly site-specific, innate trifluoromethylation usually results in the formation of position isomers.Metal-CF3 complexes are the active nucleophilic trifluoromethylation reagents.Usually the trifluoromethyl anion is generated by transmetallation of the pronucleophile resulting in a metal-bound CF3 group, e.g. CuCF3. Methyl fluorosulfonyldifluoroacetate, sodium trifluoroacetate, methyl chlorodifluoroacetate, trifluoromethyliodide, and trifluoromethyltrimethylsilane are among the most often used precursors. The preparation of CuCF3 requires moderate to high temperatures. Recently, additional precursors were introduced, enabling the formation of CuCF3 at room temperature, e.g. fluoroform, PhCOCF3, PhSO2CF3, and METHODS FOR THE SYNTHESIS OF AROMATIC TRIFLUOROMETHYL COMPOUNDS As exemplified in Scheme 2 a broad choice of functional group transformation are available for the synthesis of aromatic trifluoromethyl compounds.In the following, these protocols are briefly described.Preparation of Aromatic Trifluoromethyl Compounds by Fluorination / DeoxofluorinationChlorination of Toluene followed by Chlorine / Fluorine-ExchangeThe only process used so far for the preparation of aryl-CF3 compounds on a large scale is based on the free radical perchlorination of aromatic methyl groups followed by chlorine-fluorine exchangeby AHF (30). This process is very economical, as only low-priced reagents (Cl2, HF) and sometimes Lewis acid catalysts like FeCl3 or SbF3 are used. Due to the harsh reaction conditions (Cl2-gas, AHF at 100-180C), the scope of this reaction is limited to basic Aryl-CF3 compounds such as benzotrifluoride, chlorinated benzotrichloride or 2,4-bis(trifluoromethyl)pyridine (31). However, further functionalization of basic aryl-CF3 compounds results in a broad variety of substituted benzotrifluorides (32). Due to the use of economic raw materials and very large production volumes cost of goods are Br > Cl > F. In many cases costly aryl iodides have to be used as coupling partner as this reaction does not work with less expensive aryl bromides or chlorides. Originally, CuI was used in stoichiometric amounts (41), but also catalytic protocols have been developed (42-43).From an reagent price point of view, the most interesting Scheme 5. Methods for the formation of CuCF3.Scheme 6. One-pot Sandmeyer trifluoromethylation.Scheme 7.Coupling of aryl iodides and bromides with CuCF3 generated by decarboxylation.32 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015Trifluoromethylation of Aryl Boronic Acids and Aryl Boronates Arylboronic acids and boronates have been increasingly used as substrates for site-selective trifluoromethylation reactions.Sanford et al described a mild and practical protocol for the substitution of aryl and heteroaryl boronic acids using NaSO2CF3 (Langlois reagent) and t-butyl hydroperoxide (TBHP) as a source of CF3 radicals (48), the Beller group developed a similar protocol, but catalytic in copper (49). CF3I in the presence of a photocatalyst and visible light was used by Sanford (50). Liu and Shen (51) and the Shibata group (52) investigated the use of electrophilic reagents for trifluoromethylation of aryl boronic acids. Tognis reagent proved to be the reagent of choice for the catalytic trifluoromethylation of a broad range of substituted aryl boronic acids, c.f Scheme 11. In summary, a broad portfolio of copper-based trifluoromethylation reagents and protocols is available for the trifluoromethylation of boronic acids and boronates, providing a high level of functional group tolerance. However, it has to be noted that most of these protocols have only been applied on very small scales, so far.Innate Trifluoromethylation of Ar-H compounds Several protocols are available for the trifluoromethylation of ar-H substrates at their inherently reactive position (innate trifluoromethylation (19)). The advantage of this concept is that no prefunctionalization of the molecule is needed. The most important potential problem is the formation of undesired position isomers. For this reason most protocols focus on heterocyclic substrates. Nagib and MacMillan (58) reported a mild method for the trifluoromethylation of non-activated arenes and heteroarenes via a radical- mechanism using a photocatalyst and irradiation by a household bulb. Ritter et. al. (16) developed a protocol for the direct trifluoromethylation of electron-neutral to electron-rich arenes using a novel 1:1 adduct of CF3I with tetramethylguanidine (TMG), c.f. Scheme 13. Because the trifluoromethyl radical is known to be an electrophile, the scope of these methods is limited to electron-neutral to electron-rich arenes. Scheme 13 also depicts Barans protocol for the innate carbon-hydrogen functionalization of heterocycles based on zinc trifluoromethylsulfinate (19). This protocol tolerates reactive heteroaryl halides, nitriles, ketones, esters, and even free carboxylic acids and esters, and is not sensitive to air or moisture. In 2012 the Togni group published a protocol using the electrophilic Tognis reagent and 0.05 to 0.1 equivalents of a rhenium catalyst (59). However, for regioselectivity reasons the scope of this protocol is restricted.An iron-based radical aromatic trifluoromethylation was published by Yamakawa et al in 2010 (60). A series of arenes and heteroarenes was trifluoromethylated with CF3I in DMSO in presence of 0.3 0.5 eq. FeSO4 or Cp2Fe and 2 to 10 eq. of However, more efficient catalytic systems need to be developed in order to achieve reasonable cost both for Pd and ligand input, as well as for Pd-separationGrushin et al (47) found that fluoroform-derived CuCF3 exhibits high reactivity towards aryl and heteroaryl iodides and bromides. CuCF3 is generated by reaction of [K(DMF)][Cu(OBu-t)2] (synthesized from CuCl and potassium tert.-butylate in presence of DMF) with CHF3. Upon stabilization with Et3N(HF)3 the resulting CuCF3 is stable at room temperature for days. The inexpensive fluoroform, the high yields, and the broad scope open great opportunities. However, the need for excess amounts of copper and the elaborate procedure might limit the potential for a broad industrial application of this protocol. Scheme 10 illustrates this reaction. An alternative protocol is based on the easy to handle Cu-CF3-1,10-phenanthroline complex (TrifluoromethylatorTM). The high yield for a broad choice of substituted aryl iodides might outweigh the drawback of the need for an expensive reagent and stoichiometric amounts of copper, especially for application in R&D.Scheme 8. Coupling of aryl iodides with catalytical amounts of CuCF3 generated from easy to handle trifluoromethylating reagents. Scheme 9. Pd-catalyzed trifluoromethylation of aryl chlorides.Scheme 10. Coupling of aryl iodides and bromides with CuCF3 generated from CHF3. 33 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015preparation or manufacture of a trifluoromethylated aryl or heteroaryl compound has to consider many pros and cons of the various methods. Some criteria are proposed in Table 1. Criteria for a Qualitative Rating of the Potential of Methods for Manufacturing of Trifluoromethylated Aromatic Compounds An ideal process is based on a low-cost substrate and reagent, as well as on low cost for metals, ligands, metal removal, and waste disposal. Furthermore it is high yielding, no difficult-to remove byproducts are formed, and the technology has already been scaled into at least 1 kg to 100 kg scale. Needless to say that the most important criterion for the route selection is the total production cost of the final active substance. I.e. a short synthesis route including a selective late-stage trifluoromethylation based on an expensive reagent could be more cost-efficient than a multi-stage route including a well-priced early trifluormethylation step. Many of the described reactions are catalysed by metals. Toxicity and environmental concern of metals used for trifluoromethylation decrease in the following order: Pd > Re, Ru, Ir > Cu > Zn > Fe (63).Metal price decrease in the following order: Pd, Ir >> Ru >> Cu, Zn > Fe (64).Therefore, efficient catalytic processes are mandatory for Pd, Ru, and Ir. For Cu and Zn, catalytic processes are highly desirable. However, for certain applications even the use of stoichiometric amounts of copper or zinc might be tolerable. For example a stoichiometric copper-based protocol could be favorable compared to a lower-yielding one catalytic in copper. Separation of metals from products and waste water may require additional process steps, e.g. adsorber treatment of product solutions to remove Pd (65). Whereas metal-contaminated organic solvent based waste streams can easily be incinerated (followed by metal recovery or disposal), this isnt an option for highly diluted, water-based metals wastes because of the high cost. In such cases a tailor-made metal separation by precipitation, ion-exchange, reverse-osmosis, biodegradation, or a combination of such techniques has to be developed in order to fulfil the governmental requirements (66).Based on the criteria and the colors depicted in Table 1 the H2O2. Again, regioselectivity proved to be a serious problem with many substrates. One notable exception is 5-trifluoromethyluracil. which has been produced in a 50 kg scale in a 600 L reactor (61).Recently, Brse et al disclosed a mild, metal free method for radical perfluoroalkylation of (hetero)arenes, e.g. trifluoromethylation of benzene derivatives, furanes, pyrroles, and thiophenes with trifluoroacetic anhydride in presence of urea-hydrogen peroxide (62).POTENTIAL FOR LARGE SCALE APPLICATIONThe previous chapters illustrate the enormous diversity of reagents, strategies, and protocols available for the synthesis of trifluoromethylated aromatic compounds. A chemist who has to develop a process for the Scheme 11. Cu-mediated coupling of arylboronic acids.Scheme 12. Cu-mediated coupling of arylboronic acids and aryl boronates.Scheme 13. Innate trifluoromethylation. 35 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 201536 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015of modern synthetic protocols available for laboratory scale applications, large scale synthesis of aryl-CF3 compounds still relies mainly on the traditional sequence-chlorination of a benzylic methyl group followed by halogen exchange and finally, if required, functionalization. Deoxofluorination of carboxylic acids with SF4 starts being applied on tonne scale, but this approach is still significantly more expensive than the traditional route. Modern trifluoromethylation protocols are increasingly used in research labs for the small scale preparation of novel biologically active compounds. classical methods and a selection of modern protocols have been qualitatively assessed regarding large scale application, c.f Table 2.Remarkably, only the classical process consisting of chlorination of simple toluene derivatives followed by chlorine-fluorine exchange is currently used in a multi ton scale. Three protocols have been applied on a 1 kg to 100 kg scale, the others have predominantly been used in a mmol scale. CONCLUSIONS AND OUTLOOKThe synthetic toolbox for the synthesis of aromatic trifluoromethyl compounds has dramatically grown and is still expanding. About three decades ago, only aromatic methyl groups and carboxylic acids could be converted to trifluoromethyl groups. Today, trifluoromethyl groups can be introduced by selective trifluormethlyation of aryl-halides, aryl boronic acids and boronates, aryl amines or even aryl hydrogen compounds. In addition, some of these trifluoromethylations can be performed with relatively inexpensive reagents such as CF3COONa or CHF3.There is also progress in the mechanistic understanding of trifluoromethyation reactions. Very recently, the group of Olah and Prakash characterized the trifluoromethanide anion with a [K(18-crown-6)] countercation (67) and found that CF3- possesses a significant lifetime at sub-ambient temperatures. They showed that the outcome of many nucleophilic trifluoromethylation reactions can be explained with the occurrence of the CF3- intermediate. Such mechanistic results are expected to provide a basis for the development of further novel synthetic trifluoromethylation protocols.Even though there is now a broad palette Table 1. Criteria for large-scale application. +: * s/c: substrate to catalyst ratio. SubstrateReagent CostMetal and Catalyst Cost Specific Require-ments Waste Load Toxicity, Eco-Toxicity of Metals, Reagents Status Quo of Protocol / Process Ref. Ar-CH3 Cl2 (3 eq.) AHF (3 eq.) 0 - 0.1 eq. Sb AutoclaveHClCl2, AHF100 tonnes (30) (31) (32) Ar-NH2 Umemotos reagent (1.5 eq.),t-BuONO 3 eq. Cu-CuCummol(40) Ar-NH2 t-BuONO (1 eq.) p-TSA (1.5 eq.) Me3SiCF3 (1.5 eq.) CuSCN (0.5 eq.) CuCummol(39) Ar-COOHSF4 (2.5 eq.)AHFAutoclaveSOF2 SF4, AHF 100 kg (multi-tonnes) (33) Ar-COOHArSF3 (2.5 eq.)-AutoclaveArSOFmmol(34) Ar-ClTESCF3 (2 eq.) 0.05 eq. Pd Brettphos Strictly dryPdmmol(43) Ar-I CClF2COOMe(2-4 eq.) KF (1 eq.) CuI(1-1.5 eq.) CuCu5 kg (11b) (20) (44) Ar-ICHF3 (1.5 eq.),t-BuOK, Et3N.3HF 1.5 eq. CuStrictly inertCuCummol(47) Ar-Br Ar-ITESCF3 (2 eq.)0.1eq. Cu-CuCummol(42) Ar-I TrifluoromethylatorTM (1.2 eq.) 1.2 eq. Cu-CuCummol(36) Ar-B(OH)2 CF3SO2Na (3 eq.) TBHP 1 eq. Cu- Cu CF3SO2Na Cummol(48) Ar-B(OH)2CF3I (5 eq.) 0.2 eq. Cu 0.01 eq. Ru Day-light irradiation Cu CF3I Cummol(50) Ar-B(OH)2 Tognis reagent(1.2 eq.) 0.05 eq. Cu Phen -CuCummol(51) Ar-Bpin K[B(OMe)3CF3] (2 eq.) O2Cu(OAc) 1 eq. CuCummol(25b) Het-ar-HCF3SO2Cl (1-4 eq.) 0.02 eq. Ru Phen Day-light irradiation Rummol(58) Het-ar-H CF3I (3 eq.) H2O2 (2 eq.) FeSO4 or cp2Fe (0.3 eq.) CF3ICF3I40 kg (60) (61) Het-ar-H Zn(CF3SO2)2(1-4 eq.) TBHP (3-5 eq.) ZnZnZnmmol(19) Table 2. Potential of selected trifluoromethylation methods for large scale application. Phen = 1,10-phenanthroline, Pin = pinacolato.37 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015These modern protocols allow building up aryl-CF3 compounds with substitution pattern that may be difficult to achieve using the traditional route. It is interesting to see, how such compounds will be prepared when they are needed in large quantities. Today, there are only very few examples of trifluoromethylation processes that have been developed to multi-kilogram scale. However, in the light of the progress made in recent years we expect that the situation will change and that the number of scalable and cost-competitive trifluoromethylation processes will increase in the near future.REFERENCES AND NOTES1.For reviews regarding aromatic trifluoromethylations, see:a) Kirsch, P., Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, Germany (2004); b) Ma, J.-A., Cahard, D. Strategies for nucleophilic, electrophilic, and radical trifluoromethylations, J. Fluorine Chem., 128, 975-996 (2007); c) Tomashenko, O.A., Grushin, V. V. Aromatic Trifluoromethylation with Metal Complexes, Chem. Rev., 111, 4475-4521 (2011); d) Prakash, S.G.K.S., Wang, F. Fluorine the new kingpin of drug discovery, Chimica Oggi - Chemistry Today, 30 (5), 30-36 (2012); e) Liang, T, Neumann, C.N., Ritter, T. 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