Arene/Heteroarene Trifluoromethylation: Recent

Advances

Daniela SustacOctober 19, 2011

X"CF3"

CF3

On the properties of CF3

• Fluorine = most electronegative element in the periodic table;• CF3 = similar electronegativity to Oxygen (3.5);• CF3 = 2 ½ the volume of a Me group;

ONH

F3C

fluoxetineProzacEli Lilly

O

O

ClCF3

efavirenzBristol-Myers Squibb

SO

O

H2N

NN

CF3

celecoxibCelebrex

Pf izer

F

F

F

O

N

N

NN

CF3

NH2

sitagliptinJanuvia

Merck

• Introduction of F or CF3 in a molecule substantially alters its properties: lipophilicity, metabolic stability, bioavailability;

• No known natural products (so far) that contain a CF3 group;• Nearly 20% drugs and 35% agrochemicals on market today contain one of more

fluorine atoms.

C CF3

CF3-substituted carbocation(destabilization)

FF

CF3-substituted carbanion

(negative hyperconjugation p to

-CF3 effects

(a) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (c) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (d) Shimiza, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214. (e) McClinton, M.A.; McClinton, D.A. Tetrahedron 1992, 48, 6555.

CF3 Synthesis: Brief Overview

Direct Synthesis of R-CF3

CCl3 CF3SbF3

125 C

Swarts Reaction (1892)

(a) Swarts, F. Acad. Roy. Belg. 1892, 3, 474. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975.

Other methods of direct replacement at C: R-CCl3 + HF R-CF3

RC(S)SH + XeF2

RC(O)OH + HF + SF4

R-CF3

R-CF3

Trifluoromethylations through C-C bond forming reactionsR-X + "CF3" R-CF3conditions

"CF3" CF3CF3 CF3

Nucleophilic Electrophilic Radical

Most popular

Sources of

Nucleophilic Trifluoromethyl Reagents

• Commercially available (Aldrich, $164 for 5 mL);• Initial synthesis:

• CBrFCBrF33 (Halon 1301) ozone depleting substanceozone depleting substance, banned (Montreal protocol);• Alternative synthesis by Prakash:

Side note: CFCF33Br vs. CFBr vs. CF33I vs. CFI vs. CF33HH•C-I bond breaks more easily in water than C-Br;•CF3H ozone depleting potential <1/1000 than CF3Br;•1 ton CF3H = 11 700 tons CO2.

CF3I +Me2N

Me2N

NMe2

NMe2

DMF

- 20 C to rt

Me2N

Me2+N

N+Me2

NMe2

I-

-CF3

(a) Ruppert, I.; Schlich, K.; Volgang, W. Tet. Lett. 1984, 25, 2195. (b) Prakash, G.K.S.; Krishnamurti, R.; Olah, A.G. J. Am. Chem. Soc. 1989, 111, 393. (c) Prakash, G.K.S.; Hu, J.; Olah, A.G. J. Org. Chem. 2003, 68, 4457. (d) Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W.R. Org. Lett. 2001, 3, 4271. (e) Wikipedia

Electrophilic Trifluoromethyl Reagents

• Extremely difficult to generate +CF3 ;• Two classes of reagents:

S

CF3

mCPBA

S

CF3

O

1. Tf2O

2. NaBF4 S

CF3BF4

-

Cl SCF3

O SF3+SbF6

-

Cl SCF3

FOMe

Cl SCF3

OMe

SbF6-

SbF6-

OICl

1. KOAc, MeCN

2. TMSCF3, cat Bu4N+[PhSnF2]-

OIF3C

S

CF3

A

CF3

S

O

CF3SbF6- X- -OTf

Yagupol'skii Umemoto

A = S, Se, Te, OX = BF4, OTf

Umemoto

Trifluoromethyl chalcogen salts Iodonium salts

OIF3C

Togni

(1 g $184)

(a) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (c) Yagupolskii, L.M.; Kondratenko, N.V.; Timofeeva, G.N. J. Org. Chem. USSR 1984, 20, 103. (d) Umemoto, T. Chem. Rev 2006, 96, 1757. (e) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754.

1 g $107.50 (Aldrich)

Radical Trifluoromethyl Reagents

• CFCF33II in presence of sodium dithionite (Na2S2O4)S2O42- 2 SO2

CF3I

[CF3ISO2]- I-, - SO2

CF3 Reactions

• Trifluoromethylsulfonyl derivatives activated in presence of peroxides

• N-trifluoromethyl-N-nitrosotrifluoromethanesulfonamide

(a) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (b) Langlois, B.R.; Laurent, E.; Roidot, N. Tet. Lett. 1992, 33, 1291. (c) Umemoto, T.; Ando, A. Bull. Chem. Soc. Jpn. 1986, 59, 447.

F3C N SO2CF3

NO

TNS-TfUmemoto

Outline

• RadicaRadical Trifluoromethylations (Yamakawa, Baran)

• Pd-MediatedPd-Mediated Trifluoromethylations (Grushin, Sanford, Yu, Buchwald)

• Cu-MediatedCu-Mediated Trifluoromethylations (Vicic, Amii, Hartwig, Qing, Buchwald)

• Ag-MediatedAg-Mediated Trifluoromethylations (Sanford)

Radical Trifluoromethylation Using CFCF33II

Ar-H

Fe* (30 mol %)H2O2 (2 equiv)CF3I (3 equiv)

DMSO, 40-50 CAr-CF3

NH2

CF3

o: 22%p: 13%(FeSO4)

N

OH

CF3

68%(Cp2Fe)

N

NH2

CF3

41%(Cp2Fe)

N

N

NH2

CF3

57%(FeSO4, H2SO4)

N

CF3

low yield

NH

CF3

96%(FeSO4, H2SO4)

S CF3

49%(Cp2Fe, H2SO4)

O CF3

16%(Cp2Fe)

• In general, low to moderate yields, poor regioselectivity;• Radical formed is electrophilic in nature, thus it reacts better with electron rich arenes;• Electron poor arenes are sluggish;• Method is simple and mild.

Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98.

Proposed Mechanism

Ar-H

Fe* (30 mol %)H2O2 (2 equiv)CF3I (3 equiv)

DMSO, 40-50 CAr-CF3

FeII

FeIII

H2O2

-OH + OH O

S

H3CS

CH3

O OH

HOS

Me

O

CH3CF3

H CF3

CF3

Fenton

CF3ICH3I

HomolyticAromatic

Substitution

rearomatization

(a) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (b) Uraguchi, D.; Yamamoto, K.; Otsuka, Y.; Tokuhisa, K.; Yamakawa, T. Appl. Catal. A: Gen 2008, 342, 137. (c) Bravo, A.; Bjornvik, H.-R.; Fontana, F.; Liguori, L.; Mele, A.; Minisci, F. J. Org. Chem. 1997, 62, 7128.

Innate Trifluoromethylation of Heterocycles

H CF3 H

DGCF3

CF3

M-CF3

"Innate" trifluoromethylation "Programmed" trifluoromethylation

• Innate: functionalization of the inherently reactive positions of the substrate;• Programmed: substrate prefunctionalization /directing groups.

N

tBu

N

tBu

CF3

Initial screening: over 500 conditions (oxidants, Lewis acids, solvents, PTC)

NaSO2CF3, K2S2O8, AgNO3

TFA, DCM/H2O, 50 C

20%

NaSO2CF3

Langlois reagentbenchstable solid

EDG Cu cat. tBuOOH

F3C Het CF3BaranLanglois

(a) Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411. (b) Langlois, B.R.; Laurent, E.; Roidot, N. Tet. Lett. 1991, 32, 7525.

Reaction Optimization

Het CF3Het

NaSO2CF3 (3 to 6 equiv)tBuOOH (5 to 10 equiv)

DCM/H2O, rt, 24 h

- metal additives not required (but trace in NaSO2CF3)- large excess of reagents;- reaction sensitive to stirring;- room temp, aqueous conditions;- high functional group tolerance;- 23 examples.

N

O

F3C

67% C2:C3 2.4:1

NF3C

N

44%nicotine

N

NF3C

45

70%C4:C5 2.3:1

N

N N

N

O

O

CF3

84%caffeine

HetCF3

Byproduct

Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411.

Mechanistic Considerations

• EPR studies support radical mechanism;• CF3H observed by 19F NMR.

Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411.

Positional Selectivity

N

N

NH2

5

NaSO2CF3

N

N

NH2

CF3

N

N

NH

5

Ar

50% C5:C2 4:1

Varenicline46%

Electrophilic radical trif luoromethylationNucleophilic radical arylation

ArB(OH)2, TFA

AgNO3, K2S2O8 tBuOOH

(a) Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411. (b) Seiple, I.B.; Su, S.; Rodriguez, R.A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A.L.; Baran, P.S. J. Am. Chem. Soc. 2010, 132, 13194.

Pd-MediatedPd-Mediated Trifluoromethylations:Winning Over a Difficult Reductive

Elimination

Reductive Elimination from Pd(II): Proof of Concept

O

Ph2P PPh2

Pd

Ph

I

AgF, PhH

rt, ultrasoundO

Ph2P PPh2

Pd

Ph

F

TMSCF3O

Ph2P PPh2

Pd

F3C

88% (10:1, cis:trans)with PPh3, 82% (trans only)

Xantphos

Ph

O

Ph2P PPh2

Pd

F3CPh

XantphosPhH, 80 C, 3h

PhCF3 [(Xantphos)2Pd]

100%

PhI or PPh3

C6D6, 60 Cdecomposition or inhibiton[(PPh3)2Pd(Ph)CF3]

• Other ligands (dppe, dppb, tmeda) ineffective.

Grushin, V.V.; Marshall, W.J. J. Am. Chem. Soc. 2006, 128, 12644.

Reductive Elimination from Pd(IV): Proof of Concept

PdN

N

Ar

I

1. CsF, THF, rt

2. TMSCF3, THF, rtPd

N

N

Ar

CF3

N-N =tBubpy, tmeda, dppe

130 C

nitrobenzene-d5

Ar-CF3

<5%

Consistent with previous observations

PdII(Ar)(CF3) not susceptible towards reductive elimination

• What about a PdIV species?

PdN

N

Ar

CF3

NBS/NCS

or PhI(OAc)2

Ar-CF3

<5%

Ar-X

(X = Br, Cl or OAc)

• Look for X-type ligands that will undergo slower reductive elimination than CF3.

PdN

N

Ar

CF3

N F

OTf80 C

PhNO2

PdIVN

N

Ar

OTf

CF3

FAr-CF3

Ar = p-FPh 85% p-CF3Ph 61% p-MeOPh 86% p-PhPh 83% p-MePh 85%

No Ar-F or Ar-OTf observed by F NMR.

Ball, N.D.; Kampf, J.W.; Sanford, M.S. J. Am. Chem. Soc. 2010, 132, 2878.

Pd(II) Catalyzed ortho-Trifluoromethylation

PdIILnArCF3

Oxidation

CF3

Nucleophilicattack

Ar-CHF3PdIILn PdmLn

Ar

F3C

unknown

red

elimAr-CF3PdIILn

SCF3

X

X = OTf or BF4

N

H

PdII, conditionsN

CF3

Optimized conditions: Pd(OAc)2 (10 mol%), Cu(OAc)2 (1 equiv), CF3 reagent BF4 (1.5 equiv), TFA (10 equiv), DCE, 110 C, 48 h

- Large excess of TFA required (Pd(OTFA)2 alone gave lower yields);- Stoichiometr ic amount of Cu presumably to act as Lewis acid f or sulf ur or oxidant f or Pd (exact role TBD);- Electron neutral and donating groups are well tolerated;- EWG groups result in sluggish reactions (except for Cl);

N

CF3

MeN

CF3

MeON

CF3

Cl

83% 55% 75%

CF3

N

SMe

74%

Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.

Pd(II) Catalyzed Trifluoromethylation of Aryl Chlorides

• Further optimization identifies KF as the ideal fluoride source and renders the process catalytic.

OMe

MeO PCy2

iPriPr

iPr

BrettPhos

Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science 2010, 328, 1679.

nBu

Pd BrBrettPhos

nBu

Pd CF3BrettPhos

"CF3"

nBu

CF3

• Stoichiometric transmetallation/reductive elimination studies identify TESCF3 and CsF (28%);

Cl

nBu

[allylPdCl]2 (3 mol %)BrettPhos (9 mol %)

R3SiCF3 (2 equiv)MF (2 equiv)

THF, 110 C, 20 h

CF3

nBu

CsF KF

TMSCF3

TESCF3

trace 7%

67%25%

Substrate Scope

• High tolerance of functional groups (esters, amides, acetals, nitriles, ethers, heteroarenes);

• Limitations: aldehydes, ketones, free –NH or –OH;• Ortho –substituted arenes exhibit low conversions with BrettPhos, but improved

yields with RuPhos. OMe

MeO PCy2

iPriPr

iPr

BrettPhos

Cl

R

Pd(dba)2 or [(allyl)PdCl]2 (3 mol %)BrettPhos or RuPhos (6 mol %)

TESCF3 (2 equiv), KF (2 equiv)dioxane, 130 C, 24 h

CF3

R

CF3

CO2Hex

83%

N

O

CF3

94%

N

S

CF3

90%

CF3

Me

Ph

87% (RuPhos)

NCF3

Bn

82% (RuPhos)

23 examples

PCy2

OiPriPrO

RuPhos

Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science 2010, 328, 1679.

Mechanistic Insights

Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science 2010, 328, 1679.

Trifluoromethylation of Indoles

N

Pd(OAc)2 (10 mol %)L (15 mol %)

PhI(OAc)2 (2 equiv)

TMSCF3 (4 equiv)CsF (4 equiv)

TEMPO (0.5 equiv)MeCN, rt

NCF3

NCF3

83%

NCF3

CO2Me

33%

NCF3

ClCy

67%

N

Br

39%

O

N N

O

L

CF3

• Moderate to good yields with electron neutral and EDG groups;

• Poor yields with EWG;• Radical mechanism rejected since

TEMPO increases the yield;• Competition experiments: indoles

with EDG react faster than with EWG;

Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem. Eur. J. 2011, 17, 6039.

Cu-MediatedCu-Mediated Trifluoromethylations:Understanding an Elusive “CuCF3”

Species

Early Stoichiometric Studies

2M 2CF2X2DMF

rt[CF3MX + (CF3)2M]

CuX

-80 C, rt[CF3Cu]

stable at low Tdecomposes to [CF3CF2Cu] at rtstable in presence of HMPA at rt

HMPA

Ar-I, 70 CAr-CF3

8 examples, >70%both EDG & EWG

+

M = Cd or Zn

R-X + TESCF3

KF (1.2 equiv)CuI (1.5 equiv)

DMF/NMP80 C, 24 h

R-CF3

Reaction works for aryl, benzyl, vinyl and allyl species

X = I or Br

By-product:

R-CF2CF3

(a) Wiemens, D.M.; Burton, D.J. J. Am. Chem. Soc. 1986, 108, 832. (b) Urata, H.; Fuchikami, T. Tet. Lett. 1991, 32, 91.

• Most of the early procedures unreliable, low temperatures and expensive reagents, competing Ullmann coupling, elusive “CuCF3” species.

Synthesis of a “CuCF3” ComplexiPr

iPr iPr

iPr

Cu

OtBu

TMSCF3

-HOtBu

iPr

iPr iPr

iPr

Cu

CF3

TMS

• First isolated “Cu-CF3” complex;• Silylation of unsaturated NHC backbone;• Upon heating, decomposes to LCu-CF2CF3.

CuN

N

O

O

CuN

NiPr

iPr

iPr

iPr

tBu

tBu

2 TMSCF3

THF, rtCu

N

N

iPr

iPr

CF3

extremely air sensitivecan be preformed and used in situ

• Catalytic conditions through the addition of KOtBu not feasible, since the reaction of KOtBu and TMSCF3 is too fast.

Dubinina, G.G.; Furutachi, H.; Vicic, D.A. J. Am. Chem. Soc. 2008, 130, 8600.

R-X + TMSCF3

Cu-NHC

DMF, rtR-CF3

5 eq 2 eq

Early Example of Catalytic Cu Trifluoromethylation

F S

O

O

C

F

F

O

OMeR-X

CuI (12 mol %)R-CF3 + SO2 + CO2 + MeX

R = aryl, benzyl, allyl

60 - 80 C

• Order of reactivity: I>Br>Cl;• EWG react well, no examples with EDG;• Radical scavenging studies (dinitrobenzene) suggest against a radical mechanism;• Instead, difluorocarbene pathway is proposed;• Attempts to trap difluorocarbene with an alkene (to form cyclopropane)

unsuccessful.F S

O

O

C

F

F

O

OMe

CuIF S

O

O

C

F

F

O

OCu- MeI

- CO2, SO2, Cu+:CF2 + F- CF3

-

CuI

[CF3CuI-]R-X

I- + CuX + RCF3

Chen, Q.Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun. 1989, 705.

Cu/L Catalysis

Ar-I + TESCF3

CuI/Phen complex (10 mol %)KF (2 equiv)

DMF/NMP, 60 C, 24 hAr-CF3

11 examplesEWG react wellEDG unreactive

Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.

CF3

EtO2C

CF3

O2N

CF3

Cl

CF3

Bu

89% 90% 63% 44%19F NMR yield:

N CF3

99%

Stoichiometric Cu (Hartwig)1/4[CuOtBu]4

1. phen, PhH, rt

2. TMSCF3, rt[(phen)CuCF3]

96%orange-red solid

[(phen)CuCF3]ArI (5 equiv)

DMF, rt, 18 hAr-CF3

CF3 CF3 CF3 CF3 CF3

88% 88% 86% 88%

nBu MeO Me2N

O92%

CF3 CF3 CF3 CF3

N

CF3

HOMe OMe Cl

75% 88% 90% 89% 92%

• Copper reagent tolerates a large variety of functional groups;• Under Amii’s conditions, EDG unreactive and electron neutral fairly sluggish;• Hartwig points out that the catalytic active species in Amii’s case CANNOT BE the

[(phen)CuCF3] (upon testing the above substrates under Amii’s conditons, only low yields were obtained);

• Hartwig’s system is NOT catalytic.Morimoto, H.; Tsubogo, T.; Litvinas, N.D.; Hartwig, J.F. Angew. Chem. Int. Ed. 2011, 50, 3793.

Continued

CuCl + KOtBu

1. phen (2 equiv) DMF, rt, 30 min

2. TMSCF3 (2 equiv) rt, 1h3. ArI (1 equiv) 50 C, 18 h

(2 equiv each)

Ar-CF3

In situ formation of Cu reagent with the aryl iodide as limiting reagent

Ph

CF3

BnO

CF3 CF3 CF3

Cl N

F3C

BocO

89% 95% 85% 92% 83%

I

O

[(phen)CuCF3]

DMF, rt , 18 h

CF3

O O

not observed5 equiv

91%

Mechanistic studies: against a radical pathway

Morimoto, H.; Tsubogo, T.; Litvinas, N.D.; Hartwig, J.F. Angew. Chem. Int. Ed. 2011, 50, 3793.

Oxidative Trifluoromethylation (Qing)

Ar-B(OH)2 + "CuCF3"oxidant

Ar-CF3

Ar(BOH)2 + TMSCF3

[Cu(OTf)]PhH (0.6 equiv)Phen (1.2 equiv)

KF (5 equiv), Ag2CO3 (1 equiv)K3PO4 (3 equiv), DMF, 45 C

Ar-CF3

Optimized conditions

CF3

Ph

81%

CF3

Br

70%

CF3

MeO2C

76%

CF3

O

85%

S

72%

CF3CF3

83%

CuIN

NOTf

CF3CuI

N

NCF3

ArB(OH)2

oxidantCuII

N

N

CF3

Ar

reductive

eliminationAr-CF3

Proposed Mechanism (details still TBD)

Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060.

Oxidative Trifluoromethylation (Buchwald)

Ar(BOH)2 + TMSCF3

Cu(OAc)2 (1 equiv)Phen (1.1 equiv)

CsF (2 equiv), 4 Å molec sievesDCE or iPrCN, O2, rt

Ar-CF3

2 equiv

CF3

Cl

O

67%

CF3

Br

60%

TBSO

CF3

55%

CF3HN

Boc

34%

N

F3C

44%

Senecal, D.T.; Parsons, A.T.; Buchwald, S.L. J. Org. Chem. 2011, 76, 1174.

Trifluoromethylation of Unactivated Olefins (Buchwald)

• Possible pathways for allylic trifluoromethylation:

R

R CF3

R CF3

R CF3

R CF3

• Screening of different Cu salts and electrophilic trifluoromethylation reagents identified Togni’s reagent as promising hit;

Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.

Ph

OIF3C

O CuCl (15 mol %)

MeOH, 0 C to rt

2 equiv

PhCF3

81%, E:Z >20:1

+ other trifluoromethylated side products

Trifluoromethylation of Unactivated Olefins (Buchwald)

• Final optimized conditions:OI

F3C

O [(MeCN)Cu]PF6 (15 mol %)

MeOH, 0 C to rt24 h

CF3

1.05 equiv 1 equiv

71%, E:Z 98:2

PhPh

O2NCF3

72%94:6

HOCF3

CF3

O

67%97:3

70% (Cu-thiophene carboxylate)93:7

MeO CF3

O

79%95:5

BnN CF3

Ts

73%94:6

NCF3

O

O

72%97:3

BrCF3

78%96:4

• Not compatible with: branched or cyclic olefins.

Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.

Trifluoromethylation of Unactivated Olefins (Buchwald)

Ph OIF3C

O[(MeCN)Cu]PF6 (15 mol %)

MeOH, 0 C to rt24 h

Ph

CF3

56%5:1 (E:Z)radical clock

+ other trifluoromethylated side products (unidentified)

• Alternate mechanism:

EtO2C CO2Et OIF3C

O[(MeCN)Cu]PF6 (25 mol %)

MeOH, 0 C to rt48 h

EtO2C CO2Et

F3C CF3

10%

(19F NMR)

EtO2C CO2Et

CF3

9%

(1H NMR)

+ others (4 - 8%)via 5-exo-trig

EtO2C CO2Et

CF3

or

EtO2C CO2Et

CF3

[CuI]

radical alkylcopper

Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.

Trifluoromethylation of Unactivated Olefins (Wang)

C8H17

OIF3C

O CuCl (10 mol %)

MeOH, 70 CC8H17 CF3

EtOCF3

O

87%

Et2NCF3

O

93%

N CF3

O

O

68%

CF3

44%

CF3

55% 53%

PhCF3

20 mol % CuCl

N

O

OIF3C

OCuCl (100 mol %)

MeOH, 70 C N

O CF3

44% (19F NMR)

C8H17

OIF3C

O

CuCl (10 mol %)TEMPO (1.75 equiv)

MeOH, 70 C, 10 minC8H17 CF3

1%

N

O CF3

79% (19F NMR)

Wang, X.; Ye, Y.; Zhang, S.; Feng, Y.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, asap.

Proposed Mechanism(s)

Wang, X.; Ye, Y.; Zhang, S.; Feng, Y.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, asap.

Ag-MediatedAg-Mediated Trifluoromethylations

Ag-Mediated Trifluoromethylation

AgFTMSCF3

MeCN, rt15 min

AgCF3

Ph-I

I

F3C

15%o:m:p = 1.5:1:1.2

PhH CF3

28%

Ar-H + TMSCF3

AgOTf (4 equiv)KF (4 equiv)

DCE, 85 C, 24 hAr-CF3

CF3

87%

CF3

65%o:m = 1.4:1

MeO

CF3

87%o:m:p = 2.7:1:1.2

S

CF3

72%8:1

MeN

CF3

44%20:1

5-20 equiv

• Initial studies:

• Optimization: AgOTf in presence of KF;• 14 examples, limited to EDG.

Ye, Y.; Hee Lee, S.; Sanford, M.S. Org.Lett. 2011, asap.

Mechanistic Studies

TMSCF3 AgCF3- Ag0

CF3PhH

HAS

H CF3 AgOTf

- Ag0

- HOTf

CF3

AgOTf

- TMSOTf

• Radical scavenging: nitrobenzene no effect, TEMPO 7% yield (ambiguous);FeSO4 (30 mol %)

H2O2 (2 equiv)

CF3I (3 equiv)DMSO, 40-50 C

OMe OMe

CF3

AgOTf (4 equiv)KF (4 equiv)

TMSCF3

DCE, 85 C, 24 h

OMe

CF3

26%o:m:p = 7.5:1:5

87%o:m:p = 2.7:1:1.2

Radical?

• Different ratios obtained: against a radical mechanism;• Mechanism still TBD.

• Possible radical pathway (recall TMSCF3 is a nucleophilic source of CF3, has never been shown to form a radical):

(a) Ye, Y.; Hee Lee, S.; Sanford, M.S. Org.Lett. 2011, asap. (b) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98

Conclusion

• Important advances in trifluoromethylation reactions in the past 20 years;

• In spite of these, a general, inexpensiveinexpensive, mild method still required.

Romania (1918 – 1940)

Bran Castle

Vlad the Impaler (Vlad Tepes)Ruler of Wallachia

(1431 – 1476)