update to 2012 bode research group //ethz.ch/content/dam/ethz/special-interest/chab/organic... ·...

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

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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%


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rnat

iona

l Lic

ense

.

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

update to 2012 bode research group //ethz.ch/content/dam/ethz/special-interest/chab/organic... ·...

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