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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 kJ/mol). At standard pressure and temperature fluorine (F2) 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.
N
NN
N
NH2
O
OHOH
S+Me
+H3N O-
O
N
NN
N
NH2
O
OHOH
FF-
OH
AcO
H
AcO
OTf
HHH OAc
OAc
+
NO
ON
O
O O
OK+ 18F-
OH
AcO
H
AcO
H18F
H OAc
OAc
2-[18F]fluoro-2-deoxyglucose
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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 F2 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 (CF3OF) developed by Barton. Acetyl hypofluorite was introduced in 1953, but not widely used until Rozen developed the convenient synthetic route in 1981. While CF3OF 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.
HO
OAcCH3
F2/N2
CHCl3, -78 ˚C
HO
OCH3
F
AcO
CH3
O
CH3
FCH3 CH3
H3C H3C
H3C CH3CH3H3C
CF3OF
CH3
OLDA, AcOF
OF
y.75%
N SO2PhPhO2S
F
NFSI
NN
F
Cl
F-TEDA orSelectfluor
NF
N-Fluoropyridiniumtriflate
OTf
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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 SNAr substitution of C6F6, and showed that this facilitates halogen exchange reactions at lower temperature (also see 3.1).
NF X
R1
R2
R3R4
R5
Examples:R1-5: HR1,3,5: MeR2,4: ClR1-5: ClR2-4: CF3R1,5: CH2OMe
X = OTf, BF4, SbF6, ClO4
O
OTMS
OTHP
OTBS
NF OTf
MeOH2C CH2OMeO
O
OTHP
OTBS
F
N SO2PhPhO2S
FNF
OTf
H3C
CH3
CH3 NF
OTf
NN
FN
N
F
CH3
NF
B2F7
NN
F
Cl
OTf OTf 2 BF4NFSI Selectfluor
-0.78 -0.73 -0.47 -0.37 -0.34 -0.09 -0.04Ep,red(V versus SCE)
Ep,red in V relative to the standard calomel electrode (SCE)
CH3 F-TEDA-BF4
CH3CN, reflux, 16 h
CH3F
CH3
F60% 20% AcO
CH3
H3CAcO OAc
O OAc
F-TEDA-BF4
CH3CN, rt, 15 min
O
CH3
H3CAcO OAc
O OAc
F!/" = 47:53
OLDA, NFSI
THF, -78 ˚C to rtCH3
OCH3
F neat, 150 ˚C, 5 h
OCH3
y.85%
NFSIOCH3
Fquant
o/m/p=58:5:37
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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.
nBu4NCN
FF
FF
F
F
polar aprotic solvents-35 ˚C to rt
CNNC
NCCN
CN
CNnBu4NCN
"anhydrous" TBAF
NCl Cl
anhydrous TBAF
DMSO, 20 ˚C, 1.5 h NF F
>95%
OO
H3C CH3
O
CO2CH3
PPHFO
OH3C CH3
CO2CH3
OH
F
y.49%
H3CO
H3CO
SS OHN CF3
CF3
O
TBAH2F3 (3 equiv.)NIS (2.2 equiv.)
CH2Cl2, rt H3CO
H3CO
OHN CF3
CF3
O
FF
TBAH2F3: Tetrabutylammonium dihydrogen trifluoride
SS I
FS
S I
F
Et2NSiMe3 + SF4 Et2NSF3 + TMSF
(MeOCH2CH2)2NSiMe3 + SF4 (MeOCH2CH2)2NSF3 + TMSF
Diethylaminosulfur trifluoride (DAST)
Deoxofluor
OH DeoxofluorCH2Cl2rt, 16 h
F
y.85%R OH S
N R'R'
F FFSN R'R'
O FFR
F
H DeoxofluorCH2Cl2rt, 16 h
H
y.95%
O FF
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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.
FFF
Mtl X (OTf, I, Br...)
NucleophilicFluorination
ElectrophilicFluorination
NH21) HCl, NaNO22) HBF4
N2+BF4-∆ F
NCl Cl
spray-dride KFcat. Ph4PBr
PhCN, 200 ˚C, 10 h NF F
y.56%
CuF2 450-550 ˚C
FHF Cu
O2 (400 ˚C)
H2O
H3CO
N
OCH3
CH3
H3CO
N
OCH3
CH3
F
s-BuLi (1 equiv.)NFSI (2 equiv.)
THF, -78 ˚C
y.78%
N
Br
CH3
N
Br
F
Pd(OAc)2 (10 mol%)reagent (2.5 equiv.)
benzene, mw
N FCH3
H3C CH3
BF4
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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.
Pd(OTf)2•2H2O (10 mol%)reagent (1.5-3.0 equiv.)
NMP (0.5 equiv.)
R R
NHTf NHTf
FDCE, 120 ˚C
NHTf
CH3
F0.5 h, y.82%
NHTf
Br
F2 h, y.83%
NHTf
F
F4 h, y.71%
H3C
NHTf
F
Cl
2 h, y.70%
N FCH3
H3C CH3
OTf
SnR'3
Ag2O (5 mol%)NaHCO3 (2 equiv.)NaOTf (1 equiv.)
F-TEDA-PF6 (1.5 equiv.) F
R Racetone, 65 ˚C
(R'=Me, Bu)
NN
2PF6F
Cl
F
AcO
AcO NHBocOCH3
O
O
FH H
H
CH3
y.78%
y.81%
CH3
OH
OH O
CH3
NH
H3C
AcO
O
H3C
H3C
H3CO
O O
O
OCH3
O
CH3 OF
y.65%
N
OH
N
F
y.75%
OTftBuBrettPhos (6 mol%)
[(cinnamyl)PdCl]2 (2 mol%)CsF (1.5-2.0 equiv.)
toluene
F
R R
F
y.85%(80 ˚C, 24 h)
y.73%(110 ˚C, 12 h)
BuO
ON
F
Boc N
y.75%(110 ˚C, 12 h)
F
PtBu2
OMe
MeOiPr iPr
iPr
I(tBuCN)2CuOTf (3 equiv.)
AgF (2 equiv.)
DMF, 140 ˚C, 22 h
F
R R
CH3
F
y.96%
F
Ph
OF
N
y.59%y.56%
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Fluorination of phenol
Ritter JACS 2011, 133, 11482.
4 C(sp3)-F bond formations 4.1 α-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 α-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 β-ketoester catalyzed by Ti complex
Togni ACIE 2000, 39, 4359.
OHfluorinating reagent (1.2 equiv.)
CsF (3 equiv.)
toluene
F
R R
F
y.95%(80 ˚C, 3 h
Br
F
y.86%(110 ˚C, 20 h)
y.88%(80 ˚C, 18 h)
N N
F F
iPr iPr
iPr iPr
H
ON
F
Bn
NF
y.90%(110 ˚C, 20 h)
O
OH
F
O CH3
Oy.75%
(110 ˚C, 20 h
CH3H3C
N FSO2O
CO2EtNaH
Et2O, 0 ˚C to rt
O
CO2EtF
y.63%70% ee
O
CH3
O
OH3C
iPr
iPr iPr
O
O
OH3C
iPr
iPr iPrH3C F
90% ee
catalyst (5 mol%)F-TEDA
CH3CN, rt, 15 min
NN
2BF4F
Cl
F-TEDA
OO
O O
1-Napht1-Napht 1-Napht
1-Napht
TiCl
NH3C CH3
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Enantioselective organocatalytic fluorination of α-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 π-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.
H
O N Boc
1) cat (20 mol%) NFSI THF/iPrOH, -10 ˚C
2) NaBH4, CH2Cl2HO
N Boc
Fy.85%
98% eeN
NH
OH3C
H3CH3C
Ph•DCA
NTs
Cl
NTs
FPd2(dba)3 (5 mol%)
ligand (10 mol%)AgF (1.1 equiv.)
THF, rt, 24 h
HNNHO O
PPh2 Ph2P
y.74%96% ee
H
OCl
Pd2(dba)3 (5 mol%)ligand (10 mol%)AgF (3.0 equiv.)toluene, rt, 48 h H
O
Fy.67%71% ee
b:l = >20:1
N SO2PhPhO2S
FNFSI
NN
F
Cl
Selectfluor NFPY
NF
solventhexane
THFCH3CN
H2O
63.463.363.163.5
61.061.760.962.2
76.175.475.175.3
DNF (kcal/mol)
CH3
O
OO CH3
CH3CH3
NFSI (5 equiv.)C6D6, 110 ˚C, 19 min
F
CH3y.98%
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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.
O
OOH
OO
OH
AgNO3 (20 mol%)Selectfluor (2 equiv.)
H2O, 55 ˚C, 10 hO
O
FO
OHy.71%
HN N
H
O
Boc O
O
Ph
O Fe(III)2(oxalate)3 (2 equiv.)NaBH4 (6.4 equiv.)
Selectfluor (2 equiv.)CH3CN/H2O (1:1)
0.0125M, 0 ˚C, 30 minHN N
H
O
Boc O
O
Ph
O CH3
F
y.60%
F
y.72%
Cu-catalyst (10 mol%)KB(C6F5)4 (10 mol%)
N-hydroxyphthalimide (10 mol%)Selectfluor (2.2 equiv.)
CH3CN, reflux, 2 h
NCu
N
I PhPh
Mn(TMP)Cl (6 mol%)TBAF•3H2O (0.3 equiv.)
PhIO (6 equiv.)AgF (3 equiv.)
CH3CN/CH2Cl2 (3:1)50 ˚C, 6 h
F
y.55%
N
N
N
N Mn(III)Cl
H3C
H3CCH3H3C
CH3
CH3
CH3
CH3H3CCH3
H3C
H3C
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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
OH2+Cl-N
F3C
Prozac(antidepressent)
NH
O
O
F3CCl
Efavirenz(HIV inhibitor)
NN
Me
S NH2
O
O
F3C
Celebrex(rheumatoid arthritis)
CCl3 CF3SbF3 + additive
Swarts reaction
I CF3CF3I, Cu powder
DMF, 150 ºC
McLoughlin-Thrower reaction
Mg/Hg (1:1)F3C I
Et2O, -20 ºCF3C MgI
OH
CF3MeMe
less than 20% yield
F3C M MF + CF2
M = Li, MgX
Me
O
Me
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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 TMSCF3 as a nucleophilic trifluoromethylation reagent was mainly developed by Prakash, who also improved its synthesis. TMSCF3 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 TMSCF3 was reported by Prakash in 1989. The trifluoromethylation of different carbonyl compounds upon activation of TMSCF3 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 CF3 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
TMSClBrCF3, P(NEt2)3
C6H5CN, -60 ºC to rtTMSCF3
ozone depleting highly toxic
Ruppert's synthesis
CF3H1) Ph2S2, t-BuOK
2) H2O2, HOAc
Prakash's synthesis
S CF3
O
O
TMSClMg metal
DMF, 0 ºC to rtTMSCF3
OH1) cat. TBAF THF, 0ºC to rt
2) 1M HCl, rtTMSCF3 +
O
R1 R2
OH
CF3R2R1
CF3
85%
CF3HO
77%
OHCF3
72%(1.2 equiv.)
cat. Et4NFTMSCF3 +
(1.5 equiv.)N
PhH
Ph
NH
HPh
F3CPh
86%
THF, 0ºC to rt
CsF (1.2 equiv.)TMSCF3 +
(1.1 equiv.)
77%
THF, rt
N
CF3F3C
PhHN
CF3
Ph
F3CF3C
TFA, KHF2TMSCF3 +
(1.5 equiv.)
87%
DMF, rt
NBn
MeO
HNBn
MeO
CF3
NR2
R1
HF N+ R2
R1
H TMSCF3
HF2-Me Si
MeMe
CF3
FH
F
NR2
R1
H
- TMSF - HF
HNR2
R1 CF3
N
N
TMSCF3 +
(1.5 equiv.)
TFA, KHF2
MeCN, DMF, rtN
BnHN CF3
Bn 1) H2, Pd/C HCO2H/MeOH 45 ºC
2) triphosgene sat. NHCO3/CH2Cl2 0 ªCBoc Boc
N
CF3
Boc
NC
OMesityl-MgBr
Et2O, -78 ºC to rtN
CF3
Boc
HN
OMe
MeMe
59% 63% over two steps 85%
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6.1.3 Diastereo- and enantioselective examples
The addition of TMSCF3 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 TMSCF3. 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
1) TBAT (1.1 equiv.) THF, - 55 ºC
TMSCF3 +
(1.2 equiv.)2) 4 M HCl, MeOH R1
NH3+Cl-
CF3
NSO
t-Bu
R1
NH3+Cl-
CF3
88%, dr 99:1
NH3+Cl-
CF3
92%, dr 99:1
N
NH3+Cl-
CF3
84%, dr 90:10
Ph
catalyst (0.1 equiv.)TMAF (0.1 equiv.)
TMSCF3 +
(2.0 equiv.)Toluene/CH2Cl2 (2:1)
- 60 ºC to - 50 ºCAr Me
O
MeAr
N
N+
HHO N+
H
N
OHBr-
Br-
catalyst:
F3C OH
Me
F3C OH
XX = Br: 84%, 93% ee OMe: 84%, 89% ee NO2: 97%, 52% ee
OHF3C
75%, 94% ee
O2N S-Na+
S+
CF3
OMeCl
SbF6-
+ O2N SCF3
65%
S+
CF3
OMeCl
SbF6-
Cl SCF3
O SF3+SbF6-Cl S+
CF3
F
SbF6-
OMeSynthesis of Yagupolskii reagent:
Cl SH
1) NaH, CF3Br DMF
2) m-CPBA, CH2Cl2
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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 CF3 group is bonded directly to the iodine atom. As the reagent is prepared from TMSCF3 (!), 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.
Se+
CF3OTf-
S+
CF3OTf-
S+
CF3OTf-
O2N NO2
Li
THF, -78 ºC to rt
CF3 O-Na+
O
MeDMF, -65 ºC to rt
O
O
CF3
Me
58% 84%
NH
DMF, 80 ºC NH
CF3
90%
least reactiveCF3 of reactive carbanions
and alkanethiolates
intermediateCF3 of enolates, silyl enol ethers,
enamines and sodium iodide
most reactiveCF3 of aromatic and heteroaromatics
(ring subst. of aniline, phenol, pyrrol), PPh3
75%
t-Bu
N2+
F3CO
SbF6-
hv
CH2Cl2-99 ºC to -90 ºC
O+
CF3 SbF6-
t-Bu
DIPEACH2Cl2
-90 to -10 ºC
OH
OCF3
NH2
NHCF3
93%
CH2Cl2-90 to -10 ºC
N
CH2Cl2-90 to -10 ºC
N+
CF3
SbF6-
70%
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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 (CF3I)
Haszeldine already reported in the late 1940s that CF3 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.
I
OH
O 1) MeOH, H2SO42) MeMgBr
I O
MeMe
Cl I O
MeMe
F3CKOAc, TMSCF3, TBAT
3) t-BuOCl
Synthesis of Togni reagent:
MeCN, -17 ºC
I O
MeMe
F3C PhNO2
OEt
O
K2CO3, cat. Bu4NI, cat. CuCl
CH2Cl2, rt
PhNO2
OEt
O
F3C
59%
O
EtONH2+Cl-
SH
MeOH, rt
O
EtONH2+Cl-
SCF3
99%Ph2PH
Ph2PCF3
78%
-78 ºC to rt
I OF3C
81%2) LiNTf2 (0.02 equiv.) HNTf2 (0.12 equiv.) CH2Cl2, 35 ºC
66%
O
Ph OH(75 equiv)
Zn(NTf2)2 (1.0 equiv.)
rtPh OCF3
1) SSA, HMDS
NNH
Bn
(1.1 equiv.)
NN
Bn
CF3
I OF3C
MeMe
catalyst (0.2 equiv.)CuCl (0.05 equiv.)
CHCl3, -20 ºC
O
HR
+
O
HR
CF3
O
HCF3
81%, 94% ee
O
HCF3
80%, 94% ee
NBoc
O
HCF3
85%, 96% ee
NHCbz3
catalyst:
NH
NO
MeMe
Me
Ph(2.0 equiv.)
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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.
F3C I
hv, heat orradical initiator
ethene IF3C
CF3 F3C
+CF3I
O-Li+CF3I/Et3B
THF, -78 ºC
O
CF3
n n
40-81%
CF3Icat. Ru3(CO)12
60 ºCSiMe3
SiMe3F3C
I
89%
CF3SO2Clcat. RuCl2(PPh3)3
benzene, 120 ºCR
RF3C
Cl
34-87%R = alkyl, aryl, CO2Et
[RuII]
CF3SO2Cl
[RuIII]Cl
CF3SO2
SO2CF3
RCF3
R
RCF3
Cl
[RuIII]Cl
MeO
OMe CF3SO2Clcat. RuCl2(PPh3)3
120 ºC
solventMeO
OMeCF3
71%
CF3SO2Clcat. Ru(phen)3Cl2
K2HPO4MeCN, rt
26-W light source
unactivatedarenes
H
CF3
NHBoc
80%, 2/4 3:1
CF3
Me
Me
Br
75%, 4:1
six-atomheteroarenes
X
H
N
N CF3
OMe82%
N
N
CF3
72%
Me
MeS
N CF3
87%
MeO
Y
X Hfive-atomheteroarenes
NH
CF3
94%
N
S CF3
70%
O CF3
84%
Me
NH
CF3
72%, 2/3 4:1
CF3
74%, 3/4 2:1BF3K
O
O
Me
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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 CF3 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
R1
R2 + CF3SO2Na
R1
R2 CF3
tBuOOH (7 equiv.)cat. Cu(OTf)2
MeCN/H2O, rt13-52%
OH
CF3
45%, 2/3/4 4:1:6
NHAc
CF3
29%, 3/4 1:3
Cl Cl(4 equiv.)
OH
21%CO2Me
CF3
+ CF3SO2NatBuOOH (5 equiv.)
CH2Cl2/H2O, rt
CF3SO2NatBuO CF3SO2
SO2
CF3
XF3C H
tBuOOH OH- + tBuO
Het Het
CF3
N
MeO
(3-5 equiv.)CF3
67%, 2/3 2.4:1
N
CN
CF3
48%, 2/3 2.4:1
N CF3
NMe
44%
NN
S CF3H2N
33%
N
N
CF3
MeO
O
50%
HN
HN
CF3O
O
87%
N
NNH
HN
O CF3
76%
N
N HN
CF3Cl48%
trace metal
+
tBuO-ArH
tBuOOH
OH- + tBuO
XF3C H
+OH-
H2O
X
CF3
N
NHN
CF3
N
NHN
Vareniclinebillion-dollar drug 2011
50%, 5/2 4:1
+ 1 e-
+ (CHF2SO2)2ZntBuOOH (5 equiv.)
CH2Cl2/H2O, rt(3 equiv.)N
H+Cl-
Cl
N
Cl
CF2H
previously prepared over 6 stepsfrom 2-picolinic acid (SM: 400 CHF / g)
SM: 1 CHF / g Product: 3500 CHF / g51%
NH+Cl-
BOO
MeMe
MeMe
tBuOOH (5 equiv.)
CH2Cl2/H2O, rt N
B
CF3
+ (CF3SO2)2Zn
(3 equiv.)
OO
MeMe
MeMe
50%
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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)CuCF3]. 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)CuCF3] 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-CF3-complex CuCF3 can actually be synthesized via the direct cupration of fluoroform (CF3H). 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.
Cu(OAc)2 (1.0 equiv.)1,10-phen (1.1 equiv.)TMSCF3 +
(2.0 equiv.)CsF, O2 (1 atm)DCE or i-PrCN
4 A MS, rt
B(OH)2
R1
CF3
R1
CuIINN
OAcOAc "CF3- "
CuIINN
OAcCF3
CuIINN
PhCF3
O2
PhB(OH)2
PhCF3
O
MeO
Cl
CF3
CF3
BocHN
67%
34%
NTIPS
CF3
48%
NBoc
CF3
61%
NN OMe
MeO CF3
53%S
OCF3
64%
CuIIINN
PhCF3
O2
+DMF, rt or 50 ºC
I
R1
CF3
R1 1/4 [CuOtBu]4
1) 1,10-phen (1.0 equiv)benzene, rt
2) TMSCl (1.1 equiv), rt[(phen)CuCF3]
97%
[(phen)CuCF3]
Synthesis of [(phen)CuCF3]:
(1.2 equiv.)
CF3
O
H89%
N
CF3
Cl
89%
Cl CO2EtCF3
69%
CF3n-C6H11
99%
DMF/toluene, rt
B(OH)2
R1 CF3
R1
Synthesis of CuCF3:
CuCl + 2 tBuOK DMF- KCl
[K(DMF)][Cu(OtBu)2]1) CF3H
2) stabilizationwith Et3N(HF)3
CuCF3
90%
CuCF3air (1 atm)
DMF, 50 ºC
I
R1CF3
R1
DMF, rtR1
OBr
R1
OCF3
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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 CF3 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 CF3-Pd bond is strongly polarized towards the CF3 group and therefore electron density is missing in the region where it is required for C-CF3 bond formation. 10.1 Early studies by Grushin
In 2006, Grushin showed that reductive elimination from the palladium(II) complex XanthphosPd(Ph)CF3 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
cat. [(MeCN)4Cu]PF6+MeOH, 0ºC to rt
RI OF3C
O
(1.05 equiv.)
R CF3
good yieldsE/Z > 95:5
CF3
54%, E/Z 97:3
CF3
67%, E/Z 97:3
HO
Buchwald:
CF3
72%, E/Z 97:3
N
O
O
cat. CuCl+
MeOH, 70 ºCR
I OF3C
O
(1.75 equiv.)
R CF3
good yieldsE/Z not mentioned
or determinded
Wang:
68%
N
O
O
CF3
63%
CF3C7H15O
O
CF3
97%
TBDMSO7
cat. [(MeCN)4Cu]PF6cat. 2,2'-biquinoline
+MeCN, 55 ºC
I OF3C
O CF3
(1.1 equiv.)
OHO
OHradical
alkylcopper
OH
CF3-1e-
OH
CF3+
CF3
[Cu]OH CF3
O
O
HO
OO CF3
76%
O
HO
Ph
Me
OO CF3
Ph
Me
94%, dr 2.2:1
Ph
OH
94% ee
Ph50%, 94% ee
CF3
O
Mechanism
HOO
CF3
73%
OPPh2Ph2P Pd
CF3
82º
Xantphos (1 equiv.)
benzene, 80 ºCPhCF3 + [(Xantphos)2Pd]
100%
[(Xantphos)Pd(Ph)I]
1) AgF benzene, rt, ultrasound
2) TMSCF3
88%
Update to 2012 Bode Research Group http://www.bode.ethz.ch/
This
wor
k is
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nsed
und
er a
Cre
ativ
e C
omm
ons
Attr
ibut
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Non
Com
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-Sha
reA
like
4.0
Inte
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iona
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.
10.2 First Pd-catalyzed Ar-CF3 bond-forming reaction
Four years after Grushin the group of Buchwald reported the first Pd-catalyzed Ar-CF3 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-CF3 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
+dioxane, 110 ºC
Cl
R1
CF3
R1TESCF3
(2.0 equiv.)
CF3
O
OC6H13
85%
N
82%
cat. [(allyl)PdCl]2cat. BrettPhosKF (2 equiv.)
Ph
F3C
NC
CF3
72%
BnN
CF3
76%
N
CF3
84%
LnPd0ArCl
LnPdIIClAr
TESCF3 + KFKCl + TESCl
LnPdIICF3
Ar
ArCF3
MeO
OMe
PCy2i-Pri-Pr
i-Pr
BrettPhos
+DCE, 110 ºC
R1
cat. Pd(OAc)2Cu(OAc)2 (1.0 equiv.)
TFA (10 equiv.)S+
CF3BF4-
(1.5 equiv.)H
N R1
CF3
N
CF3
N
86%
CF3
N
75%
Cl
CF3
N
78%
OMe
CF3
N
N
75%
Me
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