Transition metal catalyzed trifluoromethylation of

unactivated alkene

Presented by Ala Bunescu

30/04/2013

Why CF3?• Important impact in pharmaceutic, agrochemistry and material science:

– before 1957 no F-containing drug had been developed, our days 150 fluorinated drugs have come to market

– ~20% of all pharmaceuticals; ~30% for agrochemicals

F3C

F3C

NO2

NO2

N

O

HN O

ClF3C N N

SO2NH2

HN O

CF3

EfavirenzHIV1 treatment

Celecoxibnon-steroidal

anti-inflammatory

Fluoxetine (Prozac) antidepressant

Trifluralin herbicide

~

Diederich- Science 2007, 317, 1881; J. T. Welch, Tetrahedron 1987, 43, 3123.

What is so special about CF3?

• F enhance metabolic stability (mainly by lowering the susceptibility to cytochrome P450 enzymatic oxidation)

• Enhance protein–ligand interactions• Increased lipophilicity• High elecrtonegativity (perturbation of pKa neighbor group,

impact on bioavailability) • Small size (2.5 x Me)• Improve thermal, chemical stability of materials

Diederich, Science 2007, 317, 1881; Gouverneur, Chem. Soc. Rev. 2008, 37, 320; McClinton-Tetrahedron,1992, 6555

Methods to introduce CF3

• Nucleophilic • Electrophilic• Radical

O OHCF3

"CF3-" nucleophile

G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757; Y. Kobayashi, Tetrahedron Lett. 1979, 20, 4071; Prakash Org. Lett. 2003, 5, 3253–3256;Y. Chang, Tetrahedron Lett. 2005, 46, 3161–3164.

"CF3+" electrophile

sources of CF3-:

Ruppert's reagent: CF3TMS/ nBu4NF

PhSO2CF3 / tBuOK,

CF3CO2Na/ CuI

Kobayasy's "CuCF3 system"

O O

CF3

Y

CF3X-

R

R

R

R

Y= S, Se, Te; X= OTf, BF4

Umemoto's reagents

T. Umemoto, Tetrahedron Lett. 1990, 31, 3579; Togni, Chem. Eur. J. 2006, 12, 2579

OIF3C

X

X= O, CF3

Togni' reagents

M

- McMillan α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis

"CF3." radical

Rf-I, lightCF3

CF3I

O O

CF3

CF3I, Et3B,airMI

Ogawa-J. Org. Chem. 2004, 69, 6658; Mikami-Org. Lett., 2005,22, 4883;

McMillan-JACS, 2009, 10875

Trifluoromethylation of unactivated double bonds

• Halotrifluoromehylation • Hydrotriflorometylation• Allylic CF3• Oxytrifluoromethylation

Iodotrifluoromethylation of double bond (ATRA)

T. Fuchikami, I. Ojima, Tetrahedron Lett. 1984, 25, 303–306

Fe3(CO)12Co2(CO)8 Pd(PPh3)4

Ni(CO)2(PPh3)2 Mo(CO)5PPh3

Ag/Al2O3

ATRA: atom transfer radical addition

Iodotrifluoromethylation of double bond (ATRA)

Proposed Mechanism

Sthephenson-JACS, 2012, 8875

Chlorotrifluoromethylation (ATRA)

Yoshida- J. Chem. Soc. Perkin Trans. 1 1991, 627Kamigata J. Chem. Soc. Chem. Commun. 1989, 1559

Hydrotrifluoromethylation of unactivated double bonds

Gouverneur-JACS, 2013, 2505

Qing-ACIE, 2013,2198

Hydrotrifluoromethylation double bonds: Ru

S

CF3

Umemoto's reagents

BF4

from carvone

from quinine

Gouverneur-JACS, 2013, 2505

Hydrotrifluoromethylation of unactivated double bonds: Ru

Gouverneur-JACS, 2013, 2505

Reduction potential Umemeto reagent: -0.25VRu(bpy)3(II): 0.77VMeOH: 1.5 V

Proposed Mechanism

Hydrotrifluoromethylation of unactivated double bonds: Ag

ConditionsAgNO3(0.1 mmol), CF3SiMe3(4eq), 1,4-CHD (1 eq)PhI(OAc)2 (2eq), NaOAc (2eq) NMP, rt, N2

Qing-ACIE, 2013,2198

from 4-methyl umbelliferone

from isopulegol

from estrone

from alkyne

Hydrotrifluoromethylation of unactivated double bonds: Ag

Qing-ACIE, 2013,2198

Proposed Mechanism

Copper catalyzed allylic trifluoromethylation

Jianbo Wang-JACS, 2011,16410

Buchwald –ACIE, 2011, 9120

15 examples 44%-97%

Liu-JACS, 2011,15300,

, DMAc

S OCu

O N

0.1eq 2equiv

Copper catalyzed allylic trifluoromethylation

Buchwald

- high selectivity for the linear trifluoromethylation (in contrast to Kharasch–Sosnovsky-type oxidative alkene functionalizations)

formation of an free allylic radical is unlikely to occur

Copper catalyzed allylic trifluoromethylation

Wang

• CF3 radical involved • allyl radical wasn’t trapped using TEMPO

no evidence of the involvement of eitherallylmetal species or trifluoromethylmetal

species in the mechanism.

Copper catalyzed allylic trifluoromethylation

Heck like four memebered ring TS

regioselectivity

LiuCu(I)/ Cu(III)

Direct protonation:

Oxytrifluoromethylation of unactivated double bonds

Akita- ACIE 2012,9567

Buchwald- JACS, 2012, 12462

Sodeoka-TL, 2012, 5503Szabo-OL, 2012, 2882

Three-component Oxytrifluoromethylation of Alkenes Mediated by Photoredox Catalysts

OIF3C

O

Togni' reagents

Buchwald- JACS, 2012, 12462

Three-component Oxytrifluoromethylation of Alkenes Mediated by Photoredox Catalysts

S

CF3

Umemoto's reagents

BF4

Akita- ACIE 2012,9567

Linear alkene doesn’t react

Oxytrifluoromethylation of unactivated double bonds

Akita- ACIE 2012,9567

Kharasch–Sosnovsky