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 butylphenylsulfurtrifluoride (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 HF. Ar-SF3 compounds can be generated by reaction of by January 1, 1994. Recycled Halon 1301 and inventories diaryldisulfides with chlorine or bromine and potassium produced before 1994 are now the only legal sources of fluoride. In the deoxofluorination of carboxylic acids two supply. Because of the Montreal Protocol, the viability of CF3Br equivalents of ArSOF are generated. ArSOF recycling might for industrial application is limited to “critical uses” which will be a prerequisite for a large scale application of Ar-SF3. continue, i.e. uses that can claim to be connected with Currently, Fluolead® is only commercially available in 100 g national security (14). quantities.

Trifluoromethyl iodide (CF3I)(15) 2nd Level Reagents Trifluoromethyl iodide has been tested as an alternative to

Fluoroform (CHF3) (10) CBrF3 as a fire-suppressing agent. It is frequently utilized for Fluoroform can be prepared by chlorine-fluorine exchange of aromatic trifluoromethylation in R&D. CF3I (bp: -21°C) is not trichloromethane. However, about 20’000 tons each year are corrosive and can be handled in normal autoclaves. It is produced as byproduct in the industrial manufacturing of probably carcinogenic to humans but not acute toxic. In fluoro polymers. In research, fluoroform is used as a contrast to Halon 1301, CF3I is not covered by the Montreal trifluoromethylation reagent and as starting material for the Protocol. 5 kg quantities of CF3I are currently available for rd preparation of 3 level trifluoromethylating reagents. about USD 2000/kg. CF3I can be prepared by several Fluoroform is a non-toxic, ozone-friendly gas (bp: -82°C). It has processes, e.g. the reaction of fluoroform with iodide and 4 a warming potential of >10 compared to CO2 and a >240- oxygen. year atmospheric lifetime. Fluoroform is highly attractive as a

CF3 source from the perspective of availability and cost, and A 1:1 adduct of trifluoromethyliodide with also of ecology, safety, and atom-economy. Fluoroform is tetrammethylguainidine (CF3I-TMG) was recently disclosed as currently available for about USD 600/1 kg. an easy to handle liquid trifluoromethylating reagent. A 30g batch of the reagent stored at 0°C showed no sign of Sodium trifluoroacetate, Potassium trifluoroacetate, Methyl decomposition over two months (16). trifluoroacetate, Methyl chlorodifluoroacetate (11)

Alkaline trifluoroacetates have been described as useful Trifluoromethyltrimethylsilane (Me3SiCF3 ,TMSCF3) / reagents for trifluoromethylation by thermal decarboxylation Trifluormethyltriethylsilane (Et3SiCF3 , TESCF3)(17) in the presence of CuI. Sodium trifluoroacetate and potassium TMSCF3 (‘Ruppert-Prakash reagent’) is a stable and easy trifluoroacetate are toxic and very hygroscopic solids and to handle liquid trifluoromethylation reagent (bp: 55°C) thus difficult to handle. Methyltrifluoroacetate (MTFA) requires which has extensively been used in R&D for three high reaction temperatures (140-180°C) for the decades. It can be handled without special equipment or decarboxylative trifluoromethylation reaction. Because of the safety precautions. For R&D applications TESCF3 is often low boiling point of MTFA (43°C) such reactions have to be preferred because its higher boiling point (56-57°C at 60 performed in autoclaves. These reagents benefit from the mbar) allows higher reaction temperatures. Whereas the fact, that the precursor trifluoroacetic acid (TFA) is produced original Ruppert preparation protocol of TMSCF3 is based in large scale. TFA itself is widely used in organic chemistry, but on CF3Br (17a), Prakash et al (10b) were able to react it hasn’t been applied as a trifluoromethylating reagent so far. fluoroform with Me3SiCl at -85°C using potassium MTFA is currently available in multi-kg amounts for about USD hexamethyldisilazane (KHMDS) as a base. From a raw 60/kg, the current retail price of 1 kg TFA-Na is about USD 300. material point of view, this is a very economical process, since fluoroform is a large volume byproduct in the Apart from MTFA also methyl chlorodifluoroacetate (MCDFA) synthesis of polytetrafluoroethylene and can be used for this type of decarboxylative chemistry. Its trimethylchlorosilane is inexpensive. The most expensive advantages compared to MTFA are the lower vapor pressure raw material in this synthesis is KHMDS. From a process (bp: 79-81°C) and the lower decarboxylation temperatures point of view, the very low temperature (-85°C) seems to (80-120°C). MCDFA is a byproduct in the synthesis of TFA, its be an obstacle. The same protocol is also well suited for current retail price of 1 kg is approx. USD 500. the synthesis of TESCF3. The current price of TMSCF3 is about USD 3000/5 kg.

Trifluoromethanesulfonylchloride (Triflic chloride; CF3SO2Cl) (12) Metal trifluoromethanesulfinates (CF3SO2Na, CF3SO2K, CF3SO2Cl is a difficult to handle liquid because it is very (CF3SO2)2Zn) (18, 19) corrosive, low-boiling (bp: 30°C) and it easily hydrolyses on air. CF3SO2Na (“Langlois reagent”), CF3SO2K and (CF3SO2)2Zn (a It can be synthesized by electro fluorination of methane “Baran reagent”) are solid salts which can easily be prepared sulfonic acid of trifluoromethyl sulfonic acid (“triflic acid”) from CF3SO2Cl and handled in air in standard laboratory followed by chlorination. Triflic chloride is not yet produced as equipment without any special precaution. In combination bulk chemical. However, based on the low retail price of triflic with tert.-butyl hydroperoxide (TBHP) they have been used as acid (USD 100/1.7 kg), it certainly has the potential for a radical trifluoromethylating reagents. These reagents are reasonably priced bulk trifluoromethylating reagent. currently commercially available in 5 g to 100 g portions.

28 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 Methyl fluorosulphonyldifluoroacetate (20) examined. Variation of the boron substituent (e.g. Methyl fluorosulphonyldifluoroacetate was introduced in 1989 benzyloxy or 2-methoxyethyl) resulted in reagents with by Chen and Wu as a new trifluoromethylating reagent. It is a similar reactivity but improved thermal stability, i.e. the easy to handle liquid with a boiling point of 118°C. This tris-benzyloxy derivative decomposes at temperatures > reagent can be prepared from chloroform, HF and SO3. It is 170°C. This reagent is currently commercially available currently available for about USD 1’000/1 kg. in gram quantities.

2,2,2-Trifluoroacetophenone (21) Electrophilic trifluoromethylating reagents (26) Aryl-trifluoromethylketones such as 2,2,2-Trifluoroacetophenone In 1984, Yagupolskii and co-workers (27) successfully achieved have been described as an excellent trifluoromethyl source. electrophilic trifluoromethylation by means of 2,2,2-Trifluoroacetophenone is a liquid (bp: 153°C) that can diaryl(trifluoromethyl)sulfonium salts such as 147531-11-1. Since be easily synthesized from bulk precursors, such as fluoroform then, additional so-called “shelf-stable electrophilic and bromobenzene. Therefore this is a potential low- to trifluoromethylating reagents” have been developed and medium-cost trifluoromethylating reagent for large scale used in academic and industrial research. Figure 1 shows a application. It is currently available for about USD 1’000/1 kg. selection of such reagents.

Phenyltrifluoromethylsulphone (22) Phenyltrifluoromethylsulphone is a liquid (bp: 203-205°C) that can be easily synthesized from bulk precursors, such as sodium trifluoroacetate and benzenesulfonic chloride. Therefore this is a potential medium-cost trifluoromethylating reagent for large application. It is currently available for about USD 3’000/1 kg. Figure 1. Common reagents for electrophilic trifluoromethylation.

4th Level Reagents TM Trifluoromethylator ((Phen)Cu-CF3) (23) For example the Togni reagents can be exposed to moist air (Phen)Cu-CF3 is a convenient to handle, thermally stable, for short periods of time without any apparent alteration. single-component reagent for the trifluoromethylation of aryl Investigations of the thermal stability of Togni’s reagents I and iodides introduced by the Hartwig-group. It can be II by Novasep Synthesis (28) indicated that some samples of synthesized by the reaction of [CuOtBu]4 with Togni’s reagent II are impact-sensitive. The Togni group 1,10-phenanthroline, followed by reaction with TMSCF3. concluded that the reagents are not explosive under typical Currently TrifluoromethylatorTM is commercially available in laboratory and reaction conditions and that these reagents portions up to 100 g. do not require severe safety measures (29). It is interesting to note that Togni’s reagent II is sold by retailers as a mixture with

Trifluoromethyl-tris(triphenylphoshino)copper [(Ph3P)3Cu(CF3)] and diatomaceous earth in order to reduce explosibility. Phenanthroline-trifluoromethyltris(triphenylphosphine)copper

[(phen)Cu(PPh)3(CF3)](24) The reagents depicted in Figure 1 are commercially available [(Ph3P)3Cu(CF3)] and [(phen)Cu(PPh)3(CF3)] have been in portions up to 100 g. 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 (trifluoromethyl)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 116-118°C. Solution in polar organic solvents such as DMF, start decomposing at approx. 80°C. Accordingly, process safety both Scheme 2. Typical protocols for the preparation of trifluoromethylated aromatic for the preparation and the application compounds. Phen* = 1,10-phenanthroline. of this reagent has to be carefully

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For more information on membership www.akcongress.com contact the Flow Chemistry Society www.flowchemistrysociety.com METHODS FOR THE SYNTHESIS OF AROMATIC TRIFLUOROMETHYL companies available that offer process R&D and COMPOUNDS production of up to multi-tonne amounts of trifluoromethylated aromatic compounds by

As exemplified in Scheme 2 a broad choice of functional deoxofluorination using SF4. group transformation are available for the synthesis of Recently, 2,6-dimethyl-4-tert.-butylphenylsulfurtrifluoride aromatic trifluoromethyl compounds. (Fluolead®) was introduced as a potential, less hazardous

substitute for SF4 (34). Two equivalents of arenesulfinylfluoride In the following, these protocols are briefly described. result as a by-product that has to be separated from the benzotrifluoride product. If the by-product can be recycled, Preparation of Aromatic Trifluoromethyl Compounds by such a method could have some potential for large scale Fluorination / Deoxofluorination application. However, scope and limitations of this Chlorination of Toluene followed by Chlorine / Fluorine- transformation have not been examined so far. Exchange

The only process used so far for the preparation of aryl-CF3 Preparation of Aromatic Trifluoromethyl Compounds by compounds on a large scale is based on the free radical Trifluoromethylation (1) perchlorination of aromatic methyl groups followed by Introduction chlorine-fluorine exchange by AHF (30). This process is very Several strategies have been pursued for the introduction of the economical, as only low-priced reagents (Cl2, HF) and trifluoromethyl group into aryl residues. Baran divided them into sometimes Lewis acid catalysts like FeCl3 or SbF3 are used. two general categories: those that functionalize the inherently Due to the harsh reaction conditions (Cl2-gas, AHF at 100- reactive position of the substrate (“innate trifluoromethylation”) 180°C), the scope of this reaction is limited to basic Aryl-CF3 and those that utilize substrate prefunctionalization or a directing compounds such as benzotrifluoride, chlorinated group (“programmed trifluoromethylation”) (35). Most often, the benzotrichloride or 2,4-bis(trifluoromethyl)pyridine (31). substitution of a functional group respectively the coupling of an

However, further functionalization of basic aryl-CF3 aryl electrophile has been effected by the CuCF3 species, compounds results in a broad variety of substituted originally identified by McLoughlin and Thrower (36) and further benzotrifluorides (32). Due to the use of economic raw developed by Kobayashi et al. (37). Scheme 4 gives an overview materials and very large production volumes cost of goods of the most important aromatic trifluoromethylation concepts, are << USD 100 / kg. However, processing of AHF is limited to including nucleophilic, radical and electrophilic mechanism. specialized companies.

Deoxofluorination of Aromatic Carboxylic Acids (33) Sulfur tetrafluoride is a very reactive deoxofluorination reagent for carboxylic acids. The reaction tolerates a number of other functional groups such as phenols, amines, ethers or nitro groups and is also applicable for a broad range of heteroaromatic carboxylic acids.

Scheme 3 illustrates the scope of SF4-based deoxofluorination of aromatic carboxylic acids.

As the processing of SF4 and AHF is Scheme 4. Strategies for the introduction of the trifluoromethyl group into aryl residues. limited to specialized companies and

SF4 should be produced on-site, the large scale industrial application of this technology has Nucleophilic reagents work best with electron-deficient started quite recently. Currently, there are only a few 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 CuCF at room Scheme 3. SF4 – based deoxofluorination of carboxylic acids (33). 3 temperature, e.g. fluoroform, PhCOCF3, PhSO2CF3, and

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 31 trifluoromethylating reagents are CHF3, CF3COOR (R = Na, K, Me), and CClCF2COOMe followed by TMSCF3, FSO2CF2COOMe, and PhCOCF3. Sodium trifluoroacetate was introduced in 1981 for the copper- mediated decarboxylative trifluoromethylation of aryl iodides (44) Although already developed to large scale, such reagents

suffer from the fact that excess of salts (2 to 10 eq. of CF3COOM and 2 to 5 eq. of CuI) is needed (11e). Another issue associated with alkaline trifluormethylacetates is their hygroscopicity because moisture favors the reduction of the aromatic halides resulting in the formation of the corresponding hydrocarbons. In 1988 Carr, Chambers and Holmes (45) published the application of this protocol for a broad range of iodo- and bromo-benzenes and heterocyclic aromatic compounds.

Scheme 5. Methods for the formation of CuCF . 3 In 1989, Chen and Wu (20) described the use of methyl fluorosulphonyldifluoroacetate for the trifluoromethylation of - potassium (trifluoromethyl)trimethoxyborate. CuCF3-DMF aryl, alkenyl and benzyl halides. CuCF3I is formed upon solutions do not degrade for several days if stabilized with e.g. heating the reagent with catalytic amounts of CuI upon

Et3N(HF)3 (10a) or HCl in Et2O (21). Scheme 5 gives an formation of CO2 and SO2, c.f. Scheme 7. overview of some of the most important precursors for CuCF3.

Originally, Cu was used in stoichiometric amounts, but also catalytic protocols have been developed, c.f. the following chapters.

Trifluoromethylation of Arene Diazonium Salts In 2013 and 2014 Sandmeyer-type trifluoromethylations were described by

Fu (38), Goossen (39), and Wang (40), Scheme 7. Coupling of aryl iodides and bromides with CuCF3 generated by decarboxylation. c.f. Scheme 6. Given the fact that aromatic amines are easily accessible and therefore In 1991, Su, Duang and Chen (11b) introduced represent economic starting materials this approach is chlorodifluoraacetate (MCDFA) as a convenient particularly interesting from an industrial point of view. trifluoromethylating reagent. This protocol was successfully Goossen’s protocol looks most interesting, since it uses a sub scaled to a multi-kg scale by Mulder et al (44). A catalytic stoichiometric amount of copper, a medium-priced protocol using 3 eq. MCDFA, 1,5 eq. KF, 0.1 eq. of copper trifluoromethylating reagent (TMSCF3) and works at room thiophene-2-carboxylate and 0.1 eq. of 1,10-phenanthroline temperature. resulted in 63% isolated yield. The use of a protocol based on methyl fluorosulfonyldifluoroacetate resulted in 72% yield. Trifluoromethylation of Aryl Halogenides However, it was excluded from further development due to its

CF3Cu has widely being used for the nucleophilic substitution of high cost and limited availability. aryl halogenides by the trifluoromethyl anion. The reactivity decreases in the following order: I > Br > Cl > F. In many cases Examples of other catalytic trifluoromethylation protocols costly aryl iodides have to be used as coupling partner as this based on convenient to handle trifluoromethylating reagents reaction does not work with less expensive aryl bromides or under mild conditions include TESCF3 (42), potassium chlorides. Originally, CuI was used in stoichiometric amounts trifluoromethyltrimethoxyborate (25a), and (41), but also catalytic protocols have been developed (42-43). TrifluoromethylatorTM (23), c.f. Scheme 8.

From an reagent price point of view, the most interesting Aryl chlorides are much more preferred starting materials than aryl bromides and especially aryl iodides from an economic point of view. The nucleophilic trifluoromethylation of aryl chlorides was achieved by the Buchwald group using palladium catalysts (43), c.f. Scheme 9.

This protocol is clearly a break-through in the field of aromatic Scheme 6. One-pot Sandmeyer trifluoromethylation. trifluoromethylation.

32 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 Trifluoromethylation 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 Scheme 8. Coupling of aryl iodides with catalytical amounts of CuCF3 generated from easy to handle trifluoromethylating reagents. 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. Togni’s 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.

Scheme 9. Pd-catalyzed trifluoromethylation of aryl chlorides. In summary, a broad portfolio of copper-based trifluoromethylation reagents and protocols is available for the However, more efficient catalytic systems need to be trifluoromethylation of boronic acids and boronates, providing developed in order to achieve reasonable cost both for Pd a high level of functional group tolerance. However, it has to and ligand input, as well as for Pd-separation be noted that most of these protocols have only been applied on very small scales, so far.

Grushin et al (47) found that fluoroform-derived CuCF3 exhibits high reactivity towards aryl and heteroaryl iodides and Innate Trifluoromethylation of Ar-H compounds bromides. CuCF3 is generated by reaction of [K(DMF)] Several protocols are available for the trifluoromethylation of [Cu(OBu-t)2] (synthesized from CuCl and potassium tert.- ar-H substrates at their inherently reactive position (“innate butylate in presence of DMF) with CHF3. Upon stabilization with trifluoromethylation” (19)). The advantage of this concept is Et3N(HF)3 the resulting CuCF3 is stable at room temperature for that no prefunctionalization of the molecule is needed. The days. The inexpensive fluoroform, the high yields, and the most important potential problem is the formation of broad scope open great opportunities. However, the need for undesired position isomers. For this reason most protocols excess amounts of copper and the elaborate procedure might focus on heterocyclic substrates. Nagib and MacMillan (58) limit the potential for a broad industrial application of this reported a mild method for the trifluoromethylation of non- protocol. Scheme 10 illustrates this reaction. 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 Baran’s 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

Scheme 10. Coupling of aryl iodides and bromides with CuCF3 moisture. In 2012 the Togni group published a protocol using generated from CHF3. the electrophilic Togni’s 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 alternative protocol is based on the easy to handle Cu-CF3-1,10- phenanthroline complex (TrifluoromethylatorTM). The high yield for a An iron-based radical aromatic trifluoromethylation was broad choice of substituted aryl iodides might outweigh the published by Yamakawa et al in 2010 (60). A series of arenes drawback of the need for an expensive reagent and stoichiometric and heteroarenes was trifluoromethylated with CF3I in DMSO amounts of copper, especially for application in R&D. in presence of 0.3 – 0.5 eq. FeSO4 or Cp2Fe and 2 to 10 eq. of

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preparation 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 Scheme 11. Cu-mediated coupling of arylboronic acids. 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 Scheme 12. Cu-mediated coupling of arylboronic acids and aryl boronates. 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, Scheme 13. Innate trifluoromethylation. Zn > Fe (64).

Therefore, efficient catalytic processes are mandatory for Pd, Ru, and Ir. For Cu and Zn, H2O2. Again, regioselectivity proved to be a serious problem with many substrates. One notable exception is catalytic processes are highly desirable. However, for certain 5-trifluoromethyluracil. which has been produced in a 50 kg applications even the use of stoichiometric amounts of scale in a 600 L reactor (61). copper or zinc might be tolerable. For example a stoichiometric copper-based protocol could be favorable Recently, Bräse et al disclosed a mild, metal free method for compared to a lower-yielding one catalytic in copper. radical perfluoroalkylation of (hetero)arenes, e.g. Separation of metals from products and waste water may trifluoromethylation of benzene derivatives, furanes, pyrroles, require additional process steps, e.g. adsorber treatment of and thiophenes with trifluoroacetic anhydride in presence of product solutions to remove Pd (65). Whereas metal- urea-hydrogen peroxide (62). contaminated organic solvent based waste streams can easily be incinerated (followed by metal recovery or disposal), this isn’t an option for highly diluted, water-based metals POTENTIAL FOR LARGE SCALE APPLICATION wastes because of the high cost. In such cases a tailor-made metal separation by precipitation, ion-exchange, reverse- The previous chapters illustrate the enormous diversity of osmosis, biodegradation, or a combination of such reagents, strategies, and protocols available for the techniques has to be developed in order to fulfil the synthesis of trifluoromethylated aromatic compounds. A governmental requirements (66). chemist who has to develop a process for the Based on the criteria and the colors depicted in Table 1 the

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 35 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 OUTLOOK

The 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 Table 1. Criteria for large-scale application. +: * s/c: substrate to catalyst ratio. reagents such as CF3COONa or CHF3.

There is also progress in the mechanistic Substrate Reagent Cost Metal and Specific Waste Toxicity, Status Ref. Catalyst Require- Load Eco-Toxicity of Quo of understanding of trifluoromethyation Cost ments Metals, Protocol / Reagents Process reactions. Very recently, the group of Olah (30) Cl2 (3 eq.) 0 - 0.1 eq. and Prakash characterized the Ar-CH3 Autoclave HCl Cl2, AHF 100 tonnes (31) AHF (3 eq.) Sb (32) trifluoromethanide anion with a [K(18- Umemoto’s reagent Ar-NH2 3 eq. Cu - Cu Cu mmol (40) (1.5 eq.), t-BuONO crown-6)] countercation (67) and found - t-BuONO (1 eq.) that CF possesses a significant lifetime at CuSCN 3 Ar-NH2 p-TSA (1.5 eq.) Cu Cu mmol (39) (0.5 eq.) Me3SiCF3 (1.5 eq.) sub-ambient temperatures. They showed 100 kg that the outcome of many nucleophilic SF4, Ar-COOH SF4 (2.5 eq.) AHF Autoclave SOF2 (multi- (33) AHF tonnes) trifluoromethylation reactions can be

Ar-COOH ArSF3 (2.5 eq.) - Autoclave ArSOF mmol (34) explained with the occurrence of the 0.05 eq. Pd - Ar-Cl TESCF3 (2 eq.) Strictly dry Pd mmol (43) CF intermediate. Such mechanistic Brettphos 3

CClF2COOMe (11b) results are expected to provide a basis for CuI Ar-I (2-4 eq.) Cu Cu 5 kg (20) (1-1.5 eq.) KF (1 eq.) (44) the development of further novel synthetic Ar-I trifluoromethylation protocols. CHF3 (1.5 eq.), . 1.5 eq. Cu Strictly inert Cu Cu mmol (47) Ar-Br t-BuOK, Et3N 3HF Ar-I TESCF3 (2 eq.) 0.1eq. Cu - Cu Cu mmol (42) Even though there is now a broad palette TrifluoromethylatorTM Ar-I 1.2 eq. Cu - Cu Cu mmol (36) (1.2 eq.) of modern synthetic protocols available

CF3SO2Na (3 eq.) Cu Ar-B(OH)2 1 eq. Cu - Cu mmol (48) for laboratory scale applications, large TBHP CF3SO2Na 0.2 eq. Cu Day-light Cu scale synthesis of aryl-CF3 compounds still Ar-B(OH)2 CF3I (5 eq.) Cu mmol (50) 0.01 eq. Ru irradiation CF3I relies mainly on the traditional sequence Togni’s reagent 0.05 eq. Cu Ar-B(OH)2 - Cu Cu mmol (51) (1.2 eq.) Phen - chlorination of a benzylic methyl group

K[B(OMe)3CF3] Cu(OAc) followed by halogen exchange and Ar-Bpin (2 eq.) Cu Cu mmol (25b) 1 eq. O2 finally, if required, functionalization. 0.02 eq. Ru Day-light Het-ar-H CF3SO2Cl (1-4 eq.) Ru mmol (58) Deoxofluorination of carboxylic acids with Phen irradiation SF starts being applied on tonne scale, FeSO4 or 4 CF3I (3 eq.) (60) Het-ar-H cp2Fe CF3I CF3I 40 kg H2O2 (2 eq.) (61) but this approach is still significantly more (0.3 eq.)

Zn(CF3SO2)2 expensive than the traditional route. Het-ar-H (1-4 eq.) Zn Zn Zn mmol (19) TBHP (3-5 eq.) Modern trifluoromethylation protocols are increasingly used in research labs for the Table 2. Potential of selected trifluoromethylation methods for large scale application. Phen = 1,10-phenanthroline, Pin = pinacolato. small scale preparation of novel biologically active compounds.

36 Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015 Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, These modern protocols allow building up aryl-CF3 compounds with substitution pattern that may be difficult to achieve using Germany (2005); doi:10.1002/14356007.a11_349; e) Langlois, B. R., the traditional route. It is interesting to see, how such compounds Roques, N., “Nucleophilic trifluoromethylation of aryl halides with will be prepared when they are needed in large quantities. methyl trifluoroacetate”, J. Fluorine Chem., 128, 1318-1325 (2007). 12. Wender, P.A., Smith, T.E., Vogel, P., et al. “Trifluoromethanesulfonyl Today, there are only very few examples of trifluoromethylation Chloride”, in e-EROS Encyclopaedia of Reagents for Organic processes that have been developed to multi-kilogram scale. Synthesis (Published Online: 15 March 2007), However, in the light of the progress made in recent years we DOI: 10.1002/9780470842898.rt248.pub2. expect that the situation will change and that the number of 13. Rozen, S., Hagooly, A., “Bromotrifluoromethane”, in e-EROS scalable and cost-competitive trifluoromethylation processes will Encyclopaedia of Reagents for Organic Synthesis (Published Online: 15 increase in the near future. October 2005, DOI: 10.1002/047084289X.rn00541. 14. For information regarding regulations of ozone-depleting substances: http://ozone.unep.org/en/ (last checked on May 4th 2015). “ REFERENCES AND NOTES 15. Burton, D. J., Qui W., Sánchez-Roselló, M., et al. Trifluoroiodomethane” , in e-EROS Encyclopedia of Reagents for Organic Synthesis (Published Online: 15 September 2009), DOI: 10.1002/047084289X.rt245.pub2. 16. Sladojevich, F., McNeill, E., Börgel, J., et al., „Condensed-Phase, 1. For reviews regarding aromatic trifluoromethylations, see: Halogen-Bonded CF I and C F I Adducts for Perfluoroalkylation a) Kirsch, P., Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 3 2 5 Reactions”, Angew. Chem. Int. Ed., 54, 1-6 (2015). Germany (2004); b) Ma, J.-A., Cahard, D. “Strategies for nucleophilic, 17. For recent publications regarding CF TMS, see a) Ruppert, I., Schlich, K., electrophilic, and radical trifluoromethylations”, J. Fluorine Chem., 128, 3 Volbach, W., “Die ersten CF -substituierten organyl(chlor)silane”, 975-996 (2007); c) Tomashenko, O.A., Grushin, V. V. “Aromatic 3 Tetrahedron Letters, 25 (21), 2195-2198 (1984); b) Singh, R. P., Shreeve, J. Trifluoromethylation with Metal Complexes”, Chem. Rev., 111, 4475- M., “Nucleophilic Trifuoromethylation Reactions of Organic 4521 (2011); d) Prakash, S.G.K.S., Wang, F. “Fluorine – the new kingpin of Compounds with (Trifuoromethyl)trimethylsilane“,Tetrahedron, 56, drug discovery”, Chimica Oggi - Chemistry Today, 30 (5), 30-36 (2012); 7613-7632 (2000); b) Liu, X., Xu, C., Wang, M., et al. e) Liang, T, Neumann, C.N., Ritter, T. “Introduction of Fluorine and “Trifluoromethyltrimethylsilane: Nucleophilic Trifluoromethylation and Fluorine-Containing Functional Groups”, Angew. Chem. Int. Ed, 52, Beyond”, Chem. Rev., 115, 683-730 (2015). 8214-8264 (2013); f) Chen, P., Liu, G. “Recent Advances in Transition- 18. Langlois, B., R., Laurent, E., Roidot, N. «Trifluoromethylation of aromatic Metal-Catalyzed Trifluoromethylation and Related Transformations”, compounds with sodium trifluoromethanesulfinate under oxidative Synthesis, 45 (21), 2919-2939 (2013). conditions». Tetrahedron Letters, 32 (51), 7525-7528 (1991). 2. For information about practical concepts in Green Chemistry and 19. Fujiwara, Y., Dixon, J. A., O’Hara, F., et al. “Practical and innate Process Research & Development, see: carbon–hydrogen functionalization of heterocycles“, Nature, 492, a) Dunn, P.J., Wells, A., Williams, M., T., Green Chemistry in the 95–99 (2012). Pharmaceutical Industry, Wiley-VCH, Weinheim, Germany (2010); b) 20. Chen, Q.-Y., Wu, S.-W., „Methyl Fluorosulfonyldifluoroacetate; a New Anderson, N.G., Practical Process Research & Development, Trifluoromethylating Agent“, J. Chem. Soc., Chem. Commun., 705-706 Academic Press, London, Great Britain (2000). (1989). 3. McReynolds, K. A., Lewis, R. S., Ackerman, L.K.G., et al. 21. Serizawa, H., Aikawa, K., Mikami, K. “Direct Synthesis of a Trifluoromethyl “Decarboxylative trifluoromethylation of aryl halides using well-defined Copper Reagent from Trifluoromethyl Ketones: Application to copper–trifluoroacetate and –chlorodifluoroacetate precursors“, J. Trifluoromethylation”, Chem. Eur. J., 19, 17692-17697 (2013). Fluorine Chem., 131 (11), 1108-1112 (2010). 22. Prakash, G. K. S., Hu, J., Olah, G. A. “Alkoxide- and Hydroxide-Induced 4. Mietchen, R., Peters, D., in METHODS IN ORGANIC CHEMISTRY Nucleophilic Trifluoromethylation Using Trifluoromethyl Sulfone or (HOUBEN-WEYL) 4th. ed., Edited by Baasner B., Hagemann H., Tatlow Sulfoxide”, Org. Lett. 5 (18), 3253–3256 (2003). J.C., Georg Thieme Verlag, Stuttgart, Germany, Vol. E10a, chapter 1, 23. Morimoto, H., Tsubogo T.; Litvinas N. D.; et al. “A Broadly Applicable 95-100 (2000). Copper Reagent for Trifluoromethylations and Perfluoroalkylations of 5. Price of anhydrous hydrogen fluoride: http://de.slideshare.net/ Aryl Iodides and Bromides”, Angew. Chem. Int. Ed. 50, 3793-3798 (2011). ccminternational/average-price-of-anhydrous-hydrogen-fluoride- 24. Tomashenko, O. A., Escudero-Adán, E.C., Belmonte, M. M., et al. “Simple, remains-low-in-china (last checked on March 22nd. 2015) Stable, and Easily Accessible Well-Defined CuCF Aromatic 6. Wang, C.-L., J., “Sulfur Tetrafluoride” , in e-EROS Encyclopedia of 3 Trifluoromethylating Agents”, Angew. Chem. Int. Ed. 50, 7655-7659 (2011). Reagents for Organic Synthesis (Published Online: 15 APR 2001), 25. a) Knauber, T., Arikan, F., Röschenthaler, G.-V., et al. “Copper- DOI: 10.1002/047084289X.rs137. Catalyzed Trifluoromethylation of Aryl Iodides with Potassium 7. Fiodorova, T., Fluorine Notes, 3 (4) (1999). (Trifluoromethyl)trimethoxyborate“, Chem. Eur. J., 17, 2689-2697 (2011); 8. http://en.wikipedia.org/wiki/Sulfur_hexafluoride (last checked on b) Khan, B. A, Buba, A. E., Goossen, L. J. “Oxidative Trifluoromethylation March 23rd. 2015). of Arylboronates with Shelf-Stable Potassium(Trifluoromethyl) 9. Umemoto, T., Singh, R.P., “Arylsulfur chlorotetrafluorides as useful trimethoxyborate“, Chem. Eur. J., 18, 1577-1581 (2012). fluorinating agents: Deoxo- and dethio-fluorinations”, J. Fluorine Chem., 26. Shibata, N., Matsnev, A., Cahard, D. ”Shelf-stable electrophilic 140, 17-27 (2012). trifluoromethylating reagents: A brief historical perspective”, Beilstein J. 10. For recent publications regarding fluoroform, see a) Grushin, V. V. Org. Chem., 6, (65), (2010). “Fluoroform as a feedstock for high-value fluorochemicals: novel trends 27. Yagupol’skii, L. M., Kondratenko, N. V., Timofeeva, G. N., Zhurnal and recent developments”, Chimica Oggi - Chemistry Today, 32 (3), Organicheskoi Khimii 20, 1115-1118 (1984), English Issue: J. Org. Chem. 81-88 (2014); b) Prakash, G.K.S., Jog, P.V., Batamak, P. T. D., Olah, G.A. USSR, 20, 103 (1984). “Taming of Fluoroform: Direct Nucleophilic Trifluoromethylation of Si, B, 28. Fiederling, N., Haller, J., Schramm, H., Notification about the Explosive S, and C Centers”, Science, 338, 1324-1327 (2012). Properties of Togni’s Reagent II and one of it’s Precursors”, Organic 11. a) Matsui, K., Tobita, E., Ando, M., Kondo, K. “A convenient Process Research & Development, 17, 318-319 (2013). trifluoromethylation of aromatic halides with sodium trifluoroacetate” 29. Charpentier, J., Früh, N., Togni, A., “Electrophilic Trifluoromethylation by Chem. Lett., 12, 1719–1720 (1981); b) Su, D.-B., Duan, J.-X., Chen, Q.-Y., Use of Hypervalent Iodine Reagents”, Chem. Rev., 115, 650-682 (2015). “Methyl chlorodifluoroacetate a convenient trifluoromethylating 30. Osswald, P., Müller, F., Steinhäuser, F., German Patent, 575593 (1933), agent”, Tetrahedron Letters, 32 (52), 7689-7690 (1991); c) Burton, D. J., assigned to I.G. Farbenindustrie. Yang, Z.-Y, “Fluorinated organometallics: Perfluoroalkyl and functionalized perfluoroalkyl organometallic reagents in organic synthesis“, Tetrahedron, 48 (2), 189-275 (1992); d) Siegemund, G., Readers interested in a full list of references are invited to visit our website at Schwertfeger, W., Feiring, A., et al., “Fluorine Compounds, Organic”, www.teknoscienze.com

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