Fluorination 2012

Update to 2012 Bode Research Group http://www.bode.ethz.
ch/
Fluorination
1 Introduction
1.1 Physical properties of fluorine
Fluorine is the most electronegative element (3.98) and therefore has a really high electron affinity (328
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kJ/mol). At standard pressure and temperature fluorine (F 2) is a pale yellow gas that is extremely reactive
due to the low F-F bond energy (36.6 kcal/mol).
1.2 Fluorine in nature
Despite fluorine being the 13th most abundant element in the Earth’s crust, only 21 biosynthesized natural
molecules containing fluorine are known (a strong contrast to the thousand of natural products containing
chlorine or bromine atoms). In nature, halogenations are normally catalyzed by haloperoxidase enzymes.
However, no fluoroperoxidase is known, a consequence of the high oxidation potential of fluorine.
Additionally, the high solvation energy of the fluoride ion in aqueous media results in a tightly bound
hydration shell of water molecules around the ion that dramatically lowers its nucleophilicity. The first
recognized fluorinating enzyme, 5’-fluoro-5’-deoxyadenosine synthase, was found in bacteria Streptomyces
cattleya and probably dehydrates solvated fluorides in its active site.
O’Hagan, Nature 2002, 416, 270

Dong, Nature 2004, 427, 561
1.3 Importance of fluorine in “daily life”
Carbon-fluorine bonds have an integral role in our daily life. Fluorine uniquely affects the properties of
organic molecules through strong polar interactions. For example, the introductions of fluorine into
pharmaceuticals can make them more bioavailable, lipophilic and metabolically stable and can increase the
strength of a compound’s interaction with a target protein. Approximately 30% of all agrochemicals and 20%
of all phramaceuticals contain fluorine. In the well-known polymer polytetrafluoroethylene (Teflon) the fluorine
atoms are responsible for the low coefficient of friction and hydrophobicity the material (non-sticking coating
of cookware). Hydrochlorofluorocarbons (HCFC) are used for refrigeration and air conditioning but also for
propellants and solvents. Finally, the natural isotope 18F is the most commonly used positron-emitting isotope
for molecular positron emission tomography (PET) imaging in oncology. An effective introduction of 18F in
organic compounds is necessary as its half-life time is only 110 minutes. The most used reagent for PET
scans is 2-[18F]fluoro-2-deoxyglucose.
Update to 2012 Bode Research Group http://www.bode.ethz.ch/
2 Common Fluorinating reagents and their reactions
2.1 Electrophilic reagents
Transfer of “F+” to an electron-rich center is the fundamental process of electrophilic fluorination, and many
efforts were devoted to tame elemental fluorine and to develop new reagents based on O-F and N-F bonds.
Taylor Tetrahedron 1999, 55, 12431.
2.1.1 Elemental fluorine (F2)
The low F-F bond energy and the high energy of bonds formed with other elements make reactions of F 2
extremely exothermic, often explosive. It was reported in 1960s that reactions became controllable by
diluting F2 with an inert gas such as N2 or Ar.
Purrington Chem. Rev. 1986, 86, 997.
Patrick JOC 1988, 53, 5153.
2.1.2 O-Fluoro electrophilic reagents
An early example of O-F electrophilic reagent is fluoroxyltrifluoromethane (CF 3OF) developed by Barton.
Acetyl hypofluorite was introduced in 1953, but not widely used until Rozen developed the convenient
synthetic route in 1981. While CF 3OF can be stored at room temperature, acetyl and perfluoroacetyl
hypofluorites are less stable and are usually generated in situ from their acetate salts and F2.
Rozen Chem. Rev. 1996, 96, 1717.
Barton Chem. Commun. 1968, 806.
Rozen JOC 2001, 66, 7464.
2.1.3 N-Fluoro electrophilic reagents
Major progress in the field of electrophilic fluorination came with the advent of N-F reagents. The lower
electronegativity of nitrogen compared to oxygen and the greater strength of the N-F bond compared to the
O-F bond contribute to decrease the electrophilicity of these reagents and render them stable and
convenient to handle. Some of them are now commercially available.
Examples of commercially available N-fluoro electrophilic reagents

Pez Chem. Rev. 1996, 96, 1737.
2.1.3.1 N-Fluoropyridinium salts
This class of reagents has been explored by Umemoto. The key to the success was the discovery that non-
nucleophilic counterions were essential to their stability. The electrophilicity of reagents can be tuned by
changing substituents on the pyridine ring.
Umemoto TL 1986, 27, 4464; JACS 1990, 112, 8563; JOC, 1995, 60, 6563.
2.1.3.2 Selectfluor and derivatives
In a series of N-fluoroquinuclidines, the fluorinating ability increase with the electron-withdrawing power of
the R group (CH3, C2H5, C8H7 < CH2Cl < CF3CH2). Selectfluor (R=CH2Cl) is commercially available and has
become a very popular reagent with many applications.
Wong ACIE 2005, 44, 192.
Gilicinski J. Fluorine. Chem. 1992, 59, 157.
Banks J. Fluorine Chem. 1998, 87, 1.
2.1.3.3 Sulfonyl derivatives
In contrast to the reagents above, the N-fluorosulfonamides are neutral N-F reagents. These are stable and
can be used for a variety of selective fluorinations. N-Fluorobenzenesulfonimide (NFSI) reported by
Differding is most widely used thanks to their balance of property between stability and reactivity.
Differding Synlett 1991, 187.
2.2 Nucleophilic reagents
Fluoride is strongly solvated in protic solvents and forms tight ion pair in most aprotic solvents, so that
fluoride is a poor nucleophile in protic solvents. Ion pairing in aprotic solvents, on the other hand, must be
overcome so as to take advantage of the potent nucleophilicity of fluoride.
2.2.1 Ammonium fluoride
One solution to increase nucleophilicity of fluoride is to use sterically demanding cation that reduces ion
pairing by delocalizing positive charge (e.g. tetrabutylammonium fluoride, TBAF). Compared with other
ammonium fluoride like tetramethylammonium fluoride (TMAF), preparing anhydrous TBAF is difficult due to
their decomposition such as Hoffmann elimination even at room temperature. DiMagno reported convenient
synthetic route to anhydrous TBAF using S NAr substitution of C6F6, and showed that this facilitates halogen
exchange reactions at lower temperature (also see 3.1).
DiMango JACS 2005, 127, 2050; ACIE 2006, 45, 2720; Chem. Commun. 2007, 528.
2.2.2 HF (Olah’s reagent)
HF is highly corrosive and difficult to handle, but an addition of amines facilitates its handling (e.g. pyridinium
poly(hydrogen fluoride), PPHF, Olah’s reagent). The presence of amine also reduces the nucleophilicity of
fluoride and the activation of substrates is normally required.
Olah JOC 1979, 44, 3872; Campbell & Sainsbury TL 1989, 30, 3711.
Oxidative desulfurization-fluorination process has gained more attention as an alternative substrate

activation mode in complex molecule synthesis.
Hiyama ACIE 2005, 44, 214.
2.2.3 DAST/Deoxofluor
Pairing the hard Lewis base F- with soft Lewis acids is another solution to increase the nucleophilicity of
fluoride. Among them, S-F reagents are widely used. Commercially available reagents, DAST and
deoxofluor, are prepared from SF4, and the latter showed higher thermal stability.
Shreeve Synthesis 2002, 17, 2561
.
Middeleton JOC 1975, 40, 574.

Lal JOC 1999, 64, 7048.
Lal Chem. Commun. 1999, 215.

3 Synthesis of aryl fluorides
3.1 Early examples
Balz-Schiemann reaction
Balz & Schiemann Chem. Ber. 1927, 60, 1186.
Halogen Exchange (Halex) Process

This is a common method for the synthesis of fluorinated aromatics in industry, in which halogens serve as
leaving groups and inexpensive, inorganic fluoride sources are used as nucleophiles.
Adams & Clark Chem. Soc. Rev. 1999, 28, 225.
CuF2 catalyzed fluorination of benzene
Subramanian Science 2002, 297, 1665.
3.2 Directed fluorination

3.2.1 Directed ortho-metalation
Snieckus & Davis TL 1994, 35, 3465.
3.2.2 Pd-catalyzed
First example of Pd-catalysis with quinolone or pyridine as a directing group
Sanford JACS 2006, 128, 7134; OL 2012, 14, 4094.

Use of triflamide as a directing group

Yu JACS 2009, 131, 7520; ACIE 2011, 50, 9081.
3.3 C-F bond formation from aryl metals and aryl halides/pseudohalides
Dimeric Ag(I) catalyst for fluorination of aryl stannanes
Ritter JACS 2010, 132, 12150.

Pd(0)/Pd(II) catalysis with nucleophilic fluoride
Buchwald Science 2009, 321, 1661; ACIE 2011, 50, 8900; JACS 2011, 133, 18106.
Cationic copper-mediated fluorination of aryl iodides
Hartwig JACS 2012, 134, 10795.

Fluorination of phenol
Ritter JACS 2011, 133, 11482.
4 C(sp3)-F bond formations

4.1 -Fluorination of carbonyl compounds
The difficulty of this type of reactions stems from the fact that monofluorinated compounds are more readily
deprotonated than starting materials. Many examples utilize -branched substrates to avoid this problem.
4.1.1 Diastereoselective fluorination

First example of enantioselective fluorination using chiral N-fluorosultams as fluorinating reagents
Lang TL 1988, 29, 6087.
4.1.2 Catalytic enantioselective fluorination

First example of asymmetric fluorination of -ketoester catalyzed by Ti complex
Togni ACIE 2000, 39, 4359.

Enantioselective organocatalytic fluorination of -nonbranched aldehydes

MacMillan JACS 2005, 127, 8826.
4.2 Allylic fluorination
Transition metal catalyzed allylic substitution is a powerful and well-explored method with both carbon and
heteroatom nucleophiles. The difficulty of catalytic allylic fluorination, however, was documented. Togni
reported that the attack of fluoride on a -allyl Pd complex was thermodynamically unfavorable, making
catalytic process difficult. In addition, allylic fluoride works as a leaving group, which also renders this
process difficult.
Togni Eur. J. Inorg. Chem. 2006, 1397; Gouverneur & Brown ACIE 2009, 48, 1296.
Palladium-catalyzed asymmetric allylic fluorination of acyclic and cyclic halides
Doyle JACS 2010, 132, 17402; JACS 2011, 133, 15902.
4.3 Fluorinations involving alkyl radical
Computational studies showed that NFSI and Selectfluor have low N-F homolytic bond dissociation energies,
which are independent of the dielectric properties of the medium. These reagents reacted with alkyl radicals
generated from corresponding peroxides under either thermal or photolytic condition.
DFT-Calculated N-F Bond Dissociation Energies
Sammis JACS 2012, 134, 4026.

Decarboxylative fluorination of aliphatic carboxylic acids was reported with catalytic amount of Ag(I) and
Selectfluor.
Li JACS 2012, 134, 10401.
Fe(III)/NaBH4-medicated hydrofluorination of unactivated alkenes was reported with Selectfluor as a source

of fluoride radical.
Boger JACS 2012, 134, 13588.

Fluorination of aliphatic C-H
Cu(I)/KB(C6F5)4 catalysis with Selectfluor
Lectka ACIE 2012, 51, 10580.
Mn/Porphyrin catalysis with AgF/TBAF•3H2O
Groves Science 2012, 337, 1322.

5 Trifluoromethylation
5.1 Introduction
The incorporation of a trifluoromethyl group (CF3) into organic compounds has become one of the fastest
growing research areas in the last 20 years. The main reason for the interest in trifluoromethylated
compounds is that the introduction of CF3 groups can substantially enhance the metabolic stability of a drug
candidate compared to its non-fluorinated analogous. Furthermore the fluorinated derivatives often exhibit
improved bioavailability and increased lipophilicity, which leads to a facilitated cell membrane penetration.
Trifluoromethyl groups are distinct from other alkyl groups such as the methyl group, both in terms of
electronic structure and reactivity. The CF3 group has the same electronegativity as chlorine (3.2) and is
similar in size to an isopropyl (i-Pr) group (bioisostere). Therefore, the trifluoromethyl group should be
considered as a distinct functional group rather than a substituted methyl group.
5.2 Early examples
Early examples of trifluoromethylation reactions relied on the conversion of chlorinated compounds into their
fluorinated derivatives. The most used reagents for this kind of transformation were anhydrous HF and
antimony trifluoride (SbF3, Swarts method). The use of HF for trifluoromethylation processes is still used
nowadays at times, because no by products are formed during this reaction (besides HCl). Another early
example is the Cu-promoted coupling reaction between an aryl halide and trifluoroiodomethane, known as
the McLoughlin-Thrower reaction.
Swarts, Bull. Acad. Roy. Belg. 1892, 24, 309

Kobayashi, TL 1969, 47, 4095
Approaches for the trifluoromethylation of organic substrates can be divided into three major categories:
Nucleophilic, electrophilic and radical trifluoromethylation, depending on the used reagents.
6 Nucleophilic trifluoromethylation
The easiest way to achieve nucleophilic trifluoromethylation would be the use of organometallic reagents,
such as trifluoromethyl magnesium iodide. However, the problem is that the generated trifluoromethyl anion
decomposes rapidly and irreversibly to the fluoride salt and difluoromethyl carbene (α-elimination).
Therefore, other reagents for the nucleophilic trifluoromethylation had to be developed.
Pierce, JACS 1954, 76, 474

6.1 Trimethyl(trifluoromethyl)silane (TMSCF3, Ruppert-Prakash reagent)
Trimethyl(trifluoromethyl)silane is an acid and water stable liquid and was first prepared by the group of
Ruppert in 1984. However, the use of TMSCF 3 as a nucleophilic trifluoromethylation reagent was mainly
developed by Prakash, who also improved its synthesis. TMSCF 3 is not only important as a direct
trifluoromethylating reagent, but also as a starting material for the preparation of a manifold of other
trifluoromethylating reagents and as a source of CF3 in catalytic C-CF3 bond formation. Aldrich: 30 CHF / g.
Ruppert, TL 1894, 25, 2195

Prakash, Org. Synth. 1995, 72, 232
6.1.1 Addition to carbonyl compounds
The first example of a nucleophilic trifluoromethylation with TMSCF 3 was reported by Prakash in 1989. The
trifluoromethylation of different carbonyl compounds upon activation of TMSCF 3 with a fluoride initiator was
described. The pre-coordination of the silicon atom to the carbonyl compound, followed by transfer of the
CF3 group makes this reaction possible and avoids generation of unstable CF 3 anion.
Prakash, JACS 1989, 111, 393

Prakash, JOC 1991, 56, 984
6.1.2 Addition to other electrophiles
TMSCF3 found application in the trifluoromethylation of many different electrophiles. The trifluoromethylation
of azirines and highly activated imines were reported by Laurent and Petrov.
Laurent, TL 1994, 35, 3303

Petrov, TL 2000, 41, 6959
A general method for the trifluoromethylation of unactivated imines was published in 2008 by the group of
Dilman. The reason for the success of this reaction was the switch from basic to acidic conditions: The in situ
generated anhydrous HF (from KHF2 and TFA) protonates the imine nitrogen, which leads to an increased
electrophilicity of the iminium carbon.
Dilman, Eur. J. Org. Chem. 2008, 5226

Bode, ACIE 2012, 51, 9173
6.1.3 Diastereo- and enantioselective examples
The addition of TMSCF 3 to chiral sulfinylimines allowed for the preparation of enantioenriched
trifluoromethylated amines.
Prakash, ACIE 2001, 40, 589

Prakash, JACS 2002, 124, 6538
Several groups have been working on the asymmetric trifluoromethylation of aldehydes and ketones. The
asymmetric induction was achieved by using chiral fluoride salts for the initiation of TMSCF 3. The most
successful approach, using a combination of tetramethylammonium fluoride and a cinchona alkaloid, was
published by the group of Shibata.
Kobayashi, TL 1994, 35, 3137

Caron, Synthesis 2003, 11, 1693
Shibata, OL 2007, 9, 3707 and OL 2010, 22, 5104
7 Electrophilic trifluoromethylation
Considering the inherent electronegative character of the trifluoromethyl group, the idea of a reagent in
which the CF3 group is positively charged might appear at first to be nonsensical. However, during the last
25 years several shelf-stable reagents were commercialized which allowed for the trifluoromethylation of a
variety of nucleophiles (Umpolung of the CF3 anion).
7.1 First example by Yagupolskii
The first electrophilic trifluoromethylating reagent was synthesized by Yagupolskii in 1984: Treatment of
aryltrifluoromethyl sulfoxide with SF3SbF6 and subsequent reaction of the sulfonium salt with an electron-rich
arene provided the diaryl(trifluoromethyl)sulfonium salt. Yagupolskii’s reagent was then reacted with p-nitro-
thiophenolate to give the corresponding trifluoromethyl sulfide in good yield.
Yagupolskii, J. Org. Chem. USSR 1984, 20, 103

7.2 (Trifluoromethyl)dibenzothiophenium salts (Umemoto reagent)
To broaden the substrate scope of electrophilic trifluoromethylations, Umemoto synthesized several reagents
based on a dibenzothiophenium core (also available with Se and Te). The aromatic moieties of the reagents
were substituted with EDG or EWG in order to fine-tune their electrophilicity. Matching the power of the
trifluoromethylating agent with the nucleophile made several trifluoromethylations possible that were not
accessible before. Aldrich: 180 CHF / g.
Umemoto, TL 1990, 31, 3579; JACS 1993, 115, 2156 and J. Fluorine Chem. 1999, 98, 75
A major limitation the sulfur-based electrophilic trifluoromethylating reagents is that only soft nucleophiles
can be reacted and that there is no possibility of preparing N-CF3 or O-CF3 compounds (HSAB principle). To
tackle this problem, Umemoto and co-workers synthesized a O-(trifluoromethyl)oxonium salt which acts as a
source of a hard electrophilic trifluoromethyl group. The reagent was prepared at very low temperature by
photochemical decomposition of a diazonium salt and reacted in situ with the electrophile (the reagent
decomposes already at -70 ºC!). Despite the elegance of this approach, the method suffers from several
shortcomings (e.g. all the reactions were run in a NMR tube and the products were never isolated).
Umemoto, JOC 2007, 72, 6905
7.3 Hypervalent iodine(III)-CF3 reagent (Togni reagent)
In 2006, the group of Togni at ETH reported a new family of hypervalent iodine compounds in which the CF 3
group is bonded directly to the iodine atom. As the reagent is prepared from TMSCF 3 (!), the overall reaction
can be considered a formal Umpolung of the CF3 group (from CF3- to CF3+). This new reagent could be used
for the trifluoromethylation of many nucleophiles (enolates, thiols, phosphines…). Aldrich: 450 CHF / g.
Togni, Chem. Eur. J. 2006, 12, 2579; ACIE 2007, 46, 754 and Chem. Commun. 2008, 1575
Using a slightly modified Togni reagent and in the presence of zinc(II) salts it is possible to convert primary
and secondary aliphatic alcohols into the corresponding trifluoromethyl ethers. However, tertiary alcohols
and phenols could not be O-trifluoromethylated (check a recent paper from Ritter for an elegant access to O-
trifluoromethylated phenols). Recently, Togni also reported the trifluoromethylation of various azoles. Despite
the significant interest of these N-CF3 compounds, the reaction is not easy to execute and isomeric mixtures
of products are normally obtained.
Togni, ACIE 2009, 48, 4332 and ACIE 2012, 51, 6511
Ritter, JACS 2011, 133, 13308
7.3.1 Enantioselective example
One of the few examples of enantioselective trifluoromethylation was disclosed by MacMillan in 2010. Togni
reagent in combination with the condensation of an aldehyde with a chiral imidazolidinone catalyst provided
the α-formyl CF3 product in good yield and with excellent enantioselectivity.
MacMillan, JACS 2010, 132, 4986
8 Radical trifluoromethylation
The addition of a CF3 radical to organic substrates, especially to alkenes, is an attractive way to introduce
trifluoromethyl groups. Due to their high electronegativity, the F atoms exert a strong σ-inductive effect on
the carbon radical (CF3 radical adapts a pyramidal configuration). Therefore it can be considered an
electrophilic radical with a low-lying SOMO (single occupied molecular orbital), which reacts faster with
electron-rich alkenes possessing high-lying HOMOs.
8.1 Early examples with trifluoroiodomethane (CF 3I)
Haszeldine already reported in the late 1940s that CF 3 radicals can be generated from CF3I upon heating or
irradiation. This type of intermolecular iodine atom transfer/radical addition (ATRA) using CF3I has performed
successfully with various alkenes and radical initiators.
Haszeldine, J. Soc. Chem. 1949, 2856

Utimoto, TL 1990, 31, 6391
Ojima, TL 1984, 25, 303
8.2 Trifluoromethylsulfonyl chloride (CF3SO2Cl)
From a practical point of view, experiments with gaseous CF3I can be inconvenient and the concentration of
the reagent is not easy to control. Trifluoromethylsulfonyl chloride turned out to be a valuable replacement as
a source of CF3 radicals. In the presence of RuCl2(PPh3)3 as the catalyst various alkenes, but also electron-
rich arenes, could be trifluoromethylated.
Sawada, J. Chem. Soc. Perkin Trans. 1 1991, 627

Kamigata, Chem. Lett. 1990, 649
Based on the work of Kamigata, the trifluoromethylation of different heteroarenes was described. MacMillan
showed that the photoredox catalyst Ru(phen)3Cl2 can generate the CF3 radical already at room temperature
and high yields of the trifluoromethylated heterocycles were obtained.
MacMillan, Nature 2011, 480, 224
8.3 Sodium trifluoromethanesulfinate (CF3SO2-Na+, Langlois reagent)
Langlois showed that sodium trifluoromethanesulfinate (bench-stable, inexpensive solid) can be used to
generate CF3 radicals upon oxidation with a catalytic amount of a Cu or Fe salt and in the presence of tert-
butyl hydroperoxide as a terminal stoichiometric oxidant. A wide range of electron-rich benzene derivatives
could be trifluoromethylated (“C-H activation”), however the yields were low and mixtures of regioisomers
were obtained.
Langlois, TL 1991, 51, 7525
Recently, Baran published an elegant study on the radical C-H trifluoromethylation of different heterocycles
with Langlois reagent. Compared to the seminal report of Langlois, no metal additives were needed,
although trace metals in the commercially available Langlois reagent could be responsible for the reaction
initiation. In most cases the site selectivity of the trifluoromethylation is governed by the electronics of the
heterocycle (innate functionalization). The conditions are mild and the reaction shows remarkable functional
group tolerance and broad substrate scope. Therefore, this method can be considered as the state of the art
for trifluoromethylation of heterocycles.
Baran, PNAS 2011, 108, 14411
In the course of their study, Baran and co-workers realized that zinc sulfinate salts show remarkably
enhanced reactivity compared with their sodium-derived analogues. Therefore, they synthesized several zinc
sulfinate salts, e.g. (CF3SO2)2Zn, (CHF2SO2)2Zn and (CH2CF3SO2)2Zn, as a toolkit for the C-H
functionalization of heterocycles. The reagents are all commercially available from Aldrich: 130 CHF / g.
Baran, Nature 2012, 492, 95
9 Cu-promoted/catalyzed trifluoromethylations
Copper-assisted trifluoromethylation reactions of prefunctionalized materials (“cross coupling”) have become

extremely popular in the last couple of years. The main reason for this is that copper can stabilize the CF 3
anion via coordination to it and in doing so removing electron density from the carbon atom.
9.1 Cu-mediated Ar-CF3 trifluoromethylations (cross coupling)
The oxidative trifluoromethylation of boronic acids was achieved by the groups of Qing and Buchwald. To
suppress side reactions, copper had to be used in stoichiometric fashion (plausible mechanism shown
below). In Buchwald’s case oxygen could be used as stoichiometric oxidant (in comparison with the use of
stoichiometric silver salts in Qing’s chemistry). The mild reaction conditions allowed for high functional group
compatibility.
Qing, OL 2010, 12, 5060

Buchwald, JOC 2011, 76, 1174
One of the postulated intermediates in Cu-promoted trifluoromethylations is [(phen)CuCF 3]. This complex
could be synthesized, isolated and fully characterized by the group of Hartwig. The complex is stable at room
temperature under nitrogen atmosphere for over one month. The high reactivity of [(phen)CuCF 3] as
trifluoromethylating reagent was demonstrated by the coupling with a broad range of aryl iodides.
Hartwig, ACIE 2011, 50, 3793
Recently, the group of Grushin showed that the simplest copper-CF 3-complex CuCF3 can actually be
synthesized via the direct cupration of fluoroform (CF 3H). Fluoroform is a side-product of Teflon
manufacturing and therefore really cheap and available in large quantities. This approach could be
particularly attractive for preparing trifluoromethylated compounds on an industrial scale (Ruppert-Prakash
reagent is too expensive for large scale operations). The coupling conditions are fairly mild and no additives
are necessary.
Grushin, JACS 2011, 133, 20901; ACIE 2012, 51, 7767 and JACS 2012, 134, 16167
9.2 Cu-catalyzed trifluoromethylations
In 2011, the groups of Buchwald and Wang simultaneously developed a Cu-catalyzed allylic
trifluoromethylation of unactivated terminal olefins. The reaction could proceed via a radical or electrophilic
pathway.
Buchwald, ACIE 2011, 50, 9120

Wang, JACS 2011, 133, 16410
During the course of their studies, the group of Buchwald became interested in trapping the putative
intermediate of the allylic trifluoromethylation by a nucleophile as a means of synthesizing diverse CF 3
building blocks in a step-economical fashion. They found that olefins which are substituted with oxygen
containing groups (e.g. carboxylic acids, alcohols or phenols) can undergo oxytrifluoromethylation reactions
to provide the difunctionalized products in good yields.
Buchwald, JACS 2012, 134, 12462
10 Pd-catalyzed trifluoromethylations (cross coupling)
The most challenging step in C-CF3 bond formation via Pd-catalyzed cross coupling is the reductive
elimination. For a fast reductive elimination to occur there must be sufficient overlap between the Pd-C and
Pd-CF3 σ-bond. Due to the difference in electronegativity, the CF 3-Pd bond is strongly polarized towards the
CF3 group and therefore electron density is missing in the region where it is required for C-CF 3 bond
formation.
10.1 Early studies by Grushin
In 2006, Grushin showed that reductive elimination from the palladium(II) complex XanthphosPd(Ph)CF 3 is
possible. The electron-donating capability and the wide bite-angle of the Xantphos-ligand, which brings the
phenyl and CF3 group closer together and facilitates so the reductive elimination, are responsible for the
success of this reaction. However, Grushin was never able to develop reaction conditions that allowed all
three elementary steps – oxidative addition, transmetallation and reductive elimination – to proceed in the
same reaction flask, as required for catalysis.
Grushin, JACS 2006, 128, 12644

10.2 First Pd-catalyzed Ar-CF3 bond-forming reaction
Four years after Grushin the group of Buchwald reported the first Pd-catalyzed Ar-CF 3 bond forming reaction
using the extremely bulky and electron-rich BrettPhos ligand. The reaction employs aryl chlorides and
(trifluoromethyl)triethylsilane (TESCF3) as the CF3 source. The CF3 anion is slowly generated in situ by
initiation with KF, thus reducing the potential of side reactions to occur.
Buchwald, Science 2010, 328, 1679
10.3 Ar-CF3 bond-forming reaction via C-H activation
Shortly after Buchwald, the first Ar-CF 3 bond-forming reaction directly from C-H bonds using a directing
group strategy was reported by Yu. The reaction could be performed with simple Pd(OAc) 2 and Umemoto
reagent as a CF3 source.
Yu, JACS 2010, 132, 3648

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Update to 2012 Bode Research Group http://www.bode.ethz.

1.1 Physical properties of fluorine

1.2 Fluorine in nature

O’Hagan, Nature 2002, 416, 270

1.3 Importance of fluorine in “daily life”

2.1 Electrophilic reagents

2.1.1 Elemental fluorine (F2)

Patrick JOC 1988, 53, 5153.

2.1.2 O-Fluoro electrophilic reagents

Barton Chem. Commun. 1968, 806.

Rozen JOC 2001, 66, 7464.

2.1.3 N-Fluoro electrophilic reagents

Examples of commercially available N-fluoro electrophilic reagents

2.1.3.1 N-Fluoropyridinium salts

2.1.3.2 Selectfluor and derivatives

Gilicinski J. Fluorine. Chem. 1992, 59, 157.

Banks J. Fluorine Chem. 1998, 87, 1.

2.1.3.3 Sulfonyl derivatives

Differding Synlett 1991, 187.

2.2 Nucleophilic reagents

2.2.1 Ammonium fluoride

2.2.2 HF (Olah’s reagent)

Oxidative desulfurization-fluorination process has gained more attention as an alternative substrate

Hiyama ACIE 2005, 44, 214.

Middeleton JOC 1975, 40, 574.

Lal Chem. Commun. 1999, 215.

3.1 Early examples

Balz & Schiemann Chem. Ber. 1927, 60, 1186.

Halogen Exchange (Halex) Process

Adams & Clark Chem. Soc. Rev. 1999, 28, 225.

CuF2 catalyzed fluorination of benzene

Subramanian Science 2002, 297, 1665.

3.2 Directed fluorination

Snieckus & Davis TL 1994, 35, 3465.

Sanford JACS 2006, 128, 7134; OL 2012, 14, 4094.

Use of triflamide as a directing group

Yu JACS 2009, 131, 7520; ACIE 2011, 50, 9081.

Ritter JACS 2010, 132, 12150.

Hartwig JACS 2012, 134, 10795.

Ritter JACS 2011, 133, 11482.

4 C(sp3)-F bond formations

4.1.1 Diastereoselective fluorination

Lang TL 1988, 29, 6087.

4.1.2 Catalytic enantioselective fluorination

Togni ACIE 2000, 39, 4359.

Enantioselective organocatalytic fluorination of -nonbranched aldehydes

MacMillan JACS 2005, 127, 8826.

4.2 Allylic fluorination

Palladium-catalyzed asymmetric allylic fluorination of acyclic and cyclic halides

Doyle JACS 2010, 132, 17402; JACS 2011, 133, 15902.

4.3 Fluorinations involving alkyl radical

Sammis JACS 2012, 134, 4026.

Li JACS 2012, 134, 10401.

Fe(III)/NaBH4-medicated hydrofluorination of unactivated alkenes was reported with Selectfluor as a source

Boger JACS 2012, 134, 13588.

Lectka ACIE 2012, 51, 10580.

Mn/Porphyrin catalysis with AgF/TBAF•3H2O

Groves Science 2012, 337, 1322.

5.2 Early examples

Swarts, Bull. Acad. Roy. Belg. 1892, 24, 309

Pierce, JACS 1954, 76, 474

Ruppert, TL 1894, 25, 2195