The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides

Buchwald, S. L. et al.

Department of Chemistry, MIT, Cambridge, MA 02139, USA

Science 2010, 328, 1679-1681

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  Dramatically influence the properties of organic molecules:

• Lipophilicity • Metabolic stability • Bioavailability

  Present in many pharmaceuticals and agrochemicals:

  Fluorinated active ingredients: ~20% of all newly marketed pharmaceuticals ~30% of all agrochemicals

HN O

CF3

Fluoxetine (Prozac)Eli Lilly and Company, end of the 70's

antidepressant

SH2N

O O

N NCF3

Celecoxib (Celebrex)Pfizer, 2004

anti-inflammatory

NNNC

NH2SO

CF3Cl

Cl

CF3

NN

NC

NH2SO

CF3Cl

Cl

CF3

Fipronil (active ingredient of Regent)Rhone-Poulenc, 1985-87

(marketed by BASF since 2003)broad spectrum insecticide

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  The Swarts reaction: chlorine-fluorine exchange using SbF3 or SbF5

  From benzoic acids:

Swarts, F. Bull. Soc. Chim. Belg. 1892, 24, 309

CO2HSF4

CF3

Boswell, G. A., Jr.; Ripka, W. C.; Scribner, R. M.; Tullock, C. W. Org. React 1974, 21, 1

Harsh reaction conditions not compatible with a large number of functional groups

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  Using hypervalent iodine reagents (Togni’s reagents):

Togni, A. et al. J. Fluorine Chem. 2010, 131, 951-957

NPh

NPh

2ZnBr2 (0.5 equiv)

CHCl3rt, 48 hrs

89% isolated yield4

molar ratio 4:2 = 1:2

CF3

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-  Indoles: moderate to good yields using ZnBr2 or Zn(NTf2)2 (zinc (II) bis(trifluoromethylsulfonyl)imide) and position 2 exclusively substituted (unlike usual electrophilic substitution on indoles → directing effect by the N-atom).

-  More electron-deficient N-heteroarenes (imidazole, pyridine, pyrazine): trifluoromethylation less efficient (reaction ran at 80 °C).

-  Anilines, anisoles, phenols: moderate to good yields.

Zinc salts activate the iodine reagent: 1 + ZnX2

Togni, A. et al. J. Fluorine Chem. 2010, 131, 951-957

Trifluoromethylation of Arenes – Electrophilic Methods

Umemoto’s reagents

6 Yu, J.-Q. et al. J. Am. Chem. Soc. 2010, 132, 3648-3649

Trifluoromethylation of Arenes – Electrophilic Methods

  Pd(II)-catalyzed C-H activation:

Good to moderate yields obtained with pyrimidine, imidazole, thiazole as directing

group

Limitations:

-  TFA essential for the trifluoromethylation (Pd(OTFA)2 does not work).

-  Sulfur-containing compound formed (sulfoxide from 1) which can occupy vacant

sites on Pd(II) of reduce Pd(II) to Pd(0).

-  Stoichiometric amount of oxidant Cu(OAc)2 needed to enhance the catalytic

turnover.

-  Need for a heterocyclic directing group.

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  Trifluoromethylation of anilines:

Wakselman, C.; Tordeux, M. J. Chem. Soc, Chem. Commun. 1987,1701-1703

NH2CF3Br (1.5 equiv, 3-5 bar)

Zn (0.15 equiv)SO2 (0.15 equiv)

DMFrt, Parr apparatus

56%

NH2

CF3 mixture of ortho and para

Zn + SO2 Zn + SO2

SO2 + CF3Br SO2 + CF3Br

CF3Br Br + CF3

NH2

+ CF3

NH2CF3 oxidation -H+

NH2CF3

NH2CF3

+ para isomer + para isomer + para isomer

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  The most known method: R3SiCF3 + copper + fluoride

Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91-94

-  Stoichiometric amount of CuI needed: fast formation of 4 but sluggish regeneration of CuI ⇒ not enough Cu(I) to react with 4 before its decomposition to fluoride + difluorocarbene

-  KF better than CsF or TBAF.

- Trifluoromethylation of halopyridines with Me3SiCF3 (Schlosser, M. Eur. J. Org. Chem. 2002, 327)

R3SiCF3 + F R3SiF + CF3

F CF

F+

X

R+

KF (1.2 equiv)CuI (1.5 equiv)

DMF/NMP (1/1)80 °C, 24 hrs

CF3

R(1.2 equiv)

R = p-NO2, o-Me, p-Me, p-OMe, p-ClX = I, Br

35-99%

Et3SiCF3

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  Method catalytic in copper: use of diamine ligand

Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909-1911

Trifluoromethylation of Arenes – Nucleophilic Methods

10 Oishi, M.; kondo, H.; Amii, H. Chem. Commun. 2009, 1909-1911

Trifluoromethylation of Arenes – Nucleophilic Methods

-  1,10-Phenanthroline more efficient than TMEDA or 2,2’-Bipyridine.

-  Diamine ligands in complexes 7 increase electron density at the metal centre and nucleophilicity of the CF3 moiety.

-  Bidentate ligands stabilize the soluble Cu(I) complexe by chelation.

⇒ Acceleration of the second step to regenerate sufficient amount of reusable 6.

Limited to electron-deficient aryl iodides and 2-iodoheterocycles

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So far, no classical Pd0/PdII cross-coupling cycle developed.

Potential advantages of such a cycle:

- To overcome the limitations of the nucleophilic Cu-mediated processes.

- Use of trifluoromethyl source as a transmetalating agent to avoid the need for harsh reaction conditions to replace individual substituents on benzylic carbon atoms with fluorine.

- Many known ligands can promote oxidative addition even into unactivated aryl chlorides at low temperatures → wide substrate scope.

Main problem: High activation barrier for reductive elimination which made this process unsuccessful

until now (late transition metal-CF3 bonds generally strong and inert).

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Trifluoromethylation of Arenes – Pd-Catalysis

  Previous studies on reductive elimination with Pd(II) complexes:

- Bidentate ligands yielded no or only trace amounts of the expected benzotrifluoride products: 130 °C for days: [(LL)Pd(CF3)(Ph)] (LL = dppe or dppp, cis-chelating ligands) do not produce PhCF3. 145 °C for 64 hrs: reductive elimination occurred to give PhCF3 in 10 to 60% yield.

- Xantphos as bidentate phosphine allowed reductive elimination from [XantphosPd (Ph)(CF3)] to give PhCF3 after 3 hrs at 80 °C → wide bite angle and both cis- and trans-chelating ability.

Drawback: replacement of the Xantphos ligand in 3 with trifluoromethyl ions competes with transmetalation to 4 → no catalytic system reported with this complex.

Grushin, V. V. et al. J. Am. Chem. Soc. 2006, 128, 4632 dppe: 1,2-Bis(diphenylphosphino)ethane dppp: 1,3-Bis(diphenylphosphino)propane

Grushin, V. V. et al. J. Am. Chem. Soc. 2006, 128, 12644 O

Ph2P PPh2

Xantphos

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Trifluoromethylation of Arenes – Pd-Catalysis

  Reductive elimination from Pd(IV) complexes:

Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878-2879

Preparation of Pd(II) complexes:

N-fluoro-2,4,6-trimethylpyridinium triflate (NFTPT) as oxidant to generate the PdIV intermediate (PhI(OAc)2, NCS or NBS did not work):

Advantage compared to Grushin’s method from PdII: modest to excellent yield with diverse N- and P-donor ligands.

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Trifluoromethylation of Arenes – Pd-Catalysis

  Stoichiometric transmetalation/reductive elimination studies using BrettPhos:

(BrettPhos already employed successfully in amination and fluorination cross-coupling reactions J. Am. Chem. Soc. 2008, 130, 13552 and Science 2009, 325, 1661).

  First catalytic procedure:

Low yields with other monodentate ligands (5 to 20%). No reaction with Xantphos.

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Buchwald’s Group Breakthrough

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Buchwald’s Group Breakthrough

Less bulky RuPhos 7 more appropriate for ortho-substituted products.

Wide range of functional groups tolerated, excepted aldehydes, ketones and unprotected –OH or –NH groups (protonation of the CF3 anion to form fluoroform, reaction at the silicon centre and/or

competing coordination to the Pd centre).

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Buchwald’s Group Breakthrough

Mechanistic insight

  Preparation of Pd(II)-CF3 complexes 13 and reductive elimination studied via 19F NMR:

-  Rate constants for decomposition of 13a and 13b almost identical. -  Benzotrifluorides 14 obtained in nearly quantitative yield.

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Buchwald’s Group Breakthrough – Mechanistic Insight

Reductive elimination of 13a

CO2Me

PdL CF3

13a (L = BrettPhos 6)

Reductive elimination of 13a in presence of

methyl 4-chlorobenzoate

(5 equiv)

When 13a heated in presence of an excess of methyl 4-chlorobenzoate: Complex [LPd(Ar)Cl] 12a and ArCF3 14a formed (catalytic cycle closure)

In presence or absence of aryl chloride: same yield and rate of ArCF3 formation

⇒ Classical Pd(0)/Pd(II) catalytic cycle

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  Pd-catalyzed trifluoromethylation of a wide range of aryl chlorides.

  Facilitate the introduction of CF3 groups into advanced and functionalized organic molecules at the late stage of synthetic routes.

  Nevertheless, milder reaction conditions and broader scope of substrates should render this process much more attractive:

- Application to aryl (pseudo)halides and ketone/aldehyde-containing substrates. - Catalyst development (lowered amount,…). - Use of more economically and environmentally friendly trifluoromethylating agents: TMSCF3: 2600 €/mol (Acros Org.) TESCF3: 22000 €/mol (Aldrich)