Trifluoromethylation

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Trifluoromethylation in

pharmaceutical compounds have a trifluoromethyl group incorporated: fluoxetine, mefloquine, Leflunomide, nulitamide, dutasteride, bicalutamide, aprepitant, celecoxib, fipronil, fluazinam, penthiopyrad, picoxystrobin, fluridone, norflurazon, sorafenib and triflurazin. A relevant agrochemical is trifluralin
. The development of synthetic methods for adding trifluoromethyl groups to chemical compounds is actively pursued in academic research.

History

The first to investigate trifluoromethyl groups in relationship to biological activity was F. Lehmann in 1927.[5] An early review appeared in 1958.[6] An early synthetic method was developed by Frédéric Swarts in 1892,[7] based on antimony fluoride. In this reaction benzotrichloride was reacted with SbF3 to form PhCF2Cl and PhCF3. In the 1930s

Kinetic Chemicals and IG Farben replaced SbF3 with HF
. The McLoughlin-Thrower reaction (1968) is an early coupling reaction using iodofluoroalkanes, iodoaromatic compounds and copper.[8] In 1969 Kobayashi & Kumadaki adapted their protocol for trifluoromethylations.[9][10]

McLoughlin-Thrower reaction
McLoughlin-Thrower reaction (1968)

Reagents

Trifluoromethyltrimethylsilane

Preparation of the trifluoromethyltrimethylsilane was reported by Ingo Ruppert in 1984.[11] In 1989, Prakash and Olah first reported activation of TMSCF3 by fluoride to perform nucleophilic trifluoromethylation of carbonyl compounds.[12] In the same year, Stahly described similar reactions for the synthesis of trifluoromethylated phenols and anilines.[13] Since then TMSCF3 has been widely used as a nucleophilic trifluoromethylating agent.[14][15]

An example is the trifluoromethylation of

tetrabutylammonium fluoride.[16]

Cyclohexanol trifluoromethylation
Trifluoromethylation using

trifluoromethyltrimethylsilane[16]

The substrates can be aryl halides.[17][18] Potassium (trifluoromethyl)trimethoxyborate for this purpose has been synthesised from B(OMe)3, CF3SiMe3 and KF.[19] Aryl functionalization by C-H activation has also been reported.[20][21]

Sodium trifluoroacetate

Sodium trifluoroacetate as a reagent for trifluoromethylations was introduced by Matsui in 1981. In the original scope the substrate was an aromatic halide and the metal salt copper(I)iodide.[22][23]

Trifluoromethane

Fluoroform (CF3H) has been employed as a trifluoromethylation reagent for aldehydes in combination with a strong base.[24]

Trifluoromethylation fluoroform folleas 1998
Trifluoromethylation fluoroform folleas 1998[24]

Trifluoroiodomethane

diethyl zinc and Wilkinson's catalyst:[25]

Trifluoromethylation trifluoroiodomethane
Trifluoromethylation using
diethyl zinc and Wilkinson's catalyst[25]

Trifluoromethyl sulfone

Trifluoromethyl sulfone (PhSO2CF3) and trifluoromethyl sulfoxide (PhSOCF3) can be used for trifluoromethylations of electrophiles[26]

Trifluoromethanesulfonyl chloride

Trifluoromethanesulfonyl chloride (or

photoredox catalyst and a light source at room temperature.[27]

Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

Sodium trifluoromethanesulfinate

t-butyl hydroperoxide and generally a metal and proceeds through a radical mechanism. The reagent has been applied with heterocyclic substrates[29]

Trifluorination Langlois reagent 2011
Trifluorination Langlois reagent 2011[29]

Umemoto reagents

Umemoto reagents are (trifluoromethyl)dibenzoheterocyclic salts, such as 5-(trifluoromethyl)dibenzothiophenium triflate and 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate.[30][31]

Trifluoromethyl-metal reagents

Many CF3-containing metal complexes have been prepared, and some are useful for trifluoromethylation. The most obvious reagent is CF3Li, which can be generated by lithium-iodide exchange. This compound is however unstable even at low temperatures. It degrades to

transmetallate to bis(trifluoromethyl)cadmium.[34]

Reaction types

Aromatic coupling reactions

In

aromatic compounds and metal-trifluoromethyl complexes the metal is usually copper, Pd and Ni are less prominent.[1] The reactions are stoichiometric or catalytic. In the McLoughlin-Thrower reaction (1962) iodobenzene reacts with trifluoroiodomethane (CF3I) and copper powder in dimethylformamide at 150 °C to trifluoromethylbenzene
. The intermediate in this reaction type is a perfluoromethyl-metal complex.

A

sulfonium salt[41] or the use of a trifluoromethylcopper(I) phenanthroline complex.[42] A catalytic palladium catalysed reaction was reported in 2010 using aryl halides, (trifluoromethyl)triethylsilane and allylpalladium chloride dimer[43]

Aromatic trifluoromethylation Kitazume 1982 Aromatic trifluoromethylation Oishi 2009
Aromatic trifluoromethylation Kitazume 1982[35] Aromatic catalytic

trifluoromethylation Oishi 2009[37]

Radical trifluoromethylation

In radical trifluoromethylation the active species is the trifluoromethyl

haloform have been used for this purpose[45][46][47] but in response to the Montreal Protocol alternatives such as trifluoroiodomethane have been developed as replacement.[48][49] One particular combination is CF3I / triethylborane[50][51]
Other reagents that generate the CF3 radical are sodium trifluoromethanesulfinate and bis(trifluoroacetyl) peroxide.

Trifluorododecanone synthesis 1991
Trifluoromethylation using CF3I and triethylborane.

The base is

2,6-lutidine[50]

In the CF3 radical the fluorine atom is an

trifluoroacetate/TiO2 (photochemical) and sodium trifluoromethanesulfinate
/Cu(OSO2CF3)2/tBuOOH.

Nucleophilic trifluoromethylation

In nucleophilic trifluoromethylation the active species is the CF3− anion.[54] It was, however, widely believed that the trifluoromethyl anion is a transient species and thus cannot be isolated or observed in the condensed phase. Contrary to the popular belief, the CF3 anion, with [K(18-crown-6)]+ as a countercation, was produced and characterized by Prakash and coworkers.[55] The challenges associated with observation of CF3 anion are alluded to its strong basic nature and its tendency to form pentacoordinated silicon species, such as [Me3Si(CF3)2]− or [Me3Si(F)(CF3)]−.

The reactivity of

carbonyl compounds in DMF is an example.[54] Here CF3− and DMF form an hemiaminolate adduct ([Me2NCH(O)CF3]K).[24][56][57][58]

Trifluoromethylation methyl fluorosulfonyldifluoroacetate
trifluoromethylation using methyl fluorosulfonyldifluoroacetate.

The intermediate is CF3Cu[59]

Electrophilic trifluoromethylation

In electrophilic trifluoromethylation the active trifluoromethyl donor group carries a positive charge.

sulfonium salt (Ar2S+CF3SbF6−) was developed in 1984 by reaction of an aryltrifluoromethyl sulfoxide 1 with SF3+SbF6− followed by reaction with an electron-rich arene.[63]
The reagent was used in trifluoromethylation of a thiophenolate. S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate is a commercially available and known trifluoromethylation reagent based on the same principle first documented in 1990.[64][65] In this type of compound sulfur has been replaced by oxygen, selenium and tellurium. Examples of substrates that have been investigated are pyridine, aniline, triphenylphosphine and the lithium salt of phenylacetylene.

Electrophilic Perfluoroalkylating Agents
5-(Trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate 5-(Trifluoromethyl)dibenzothiophenium tetrafluoroborate 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole
5-(Trifluoromethyl)dibenzothiophenium
trifluoromethanesulfonate 		5-(Trifluoromethyl)dibenzothiophenium tetrafluoroborate 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole

Another group of trifluoromethyl donors are

hypervalent iodine(III)[66]–CF3 reagents for example 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole.[67][68][69][70] Some of these are known as Togni reagents, such as Togni reagent II. Substrates are thiols, alcohols, phosphines, (hetero) arenes,[71] unactivated olefins[72] and unsaturated carboxylic acids.[73]

Togni reagent synth of ethyl-(R)-2-amino-3-(trifluoromethylthio)propanoate hydrochloride
Trifluoromethylation at a thiol group using hypervalent iodine [71]

The

single electron transfer as likely candidates.[62]

Asymmetric trifluoromethylation

In

saccharides,[77] and steroids
. Because Ruppert's reagent requires a tetraalkylammonium fluoride, chiral ammonium fluorides have been employed in
asymmetric catalysis.[78][79]
In the field of electrophilic trifluoromethylation an early contribution involved reaction of a metal enolate with a trifluoromethyl chalcogen salt in presence of a chiral boron catalyst.[80]

Asymmetic trifluorination Iseki 1994 Asymmetic trifluorination Caron 2003
Asymmetric trifluoromethylation Iseki 1994[78] Asymmetric trifluormethylation Caron 2003[79]

More recent examples of highly enantioselective methods for the α-trifluoromethylation of carbonyls are available through enamine catalysis of aldehydes (photoredox[81] or iodonium[82]), copper catalysis of β-ketoesters,[83] and radical addition to zirconium enolates.[84]

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