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Transition metal catalyzed trifluoromethylation of
unactivated alkene
Presented by Ala Bunescu
30/04/2013
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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.
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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
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Methods to introduce CF3
• Nucleophilic • Electrophilic• Radical
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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
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- 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
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Trifluoromethylation of unactivated double bonds
• Halotrifluoromehylation • Hydrotriflorometylation• Allylic CF3• Oxytrifluoromethylation
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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
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Iodotrifluoromethylation of double bond (ATRA)
Proposed Mechanism
Sthephenson-JACS, 2012, 8875
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Chlorotrifluoromethylation (ATRA)
Yoshida- J. Chem. Soc. Perkin Trans. 1 1991, 627Kamigata J. Chem. Soc. Chem. Commun. 1989, 1559
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Hydrotrifluoromethylation of unactivated double bonds
Gouverneur-JACS, 2013, 2505
Qing-ACIE, 2013,2198
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Hydrotrifluoromethylation double bonds: Ru
S
CF3
Umemoto's reagents
BF4
from carvone
from quinine
Gouverneur-JACS, 2013, 2505
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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
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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
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Hydrotrifluoromethylation of unactivated double bonds: Ag
Qing-ACIE, 2013,2198
Proposed Mechanism
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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
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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
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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.
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Copper catalyzed allylic trifluoromethylation
Heck like four memebered ring TS
regioselectivity
LiuCu(I)/ Cu(III)
Direct protonation:
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Oxytrifluoromethylation of unactivated double bonds
Akita- ACIE 2012,9567
Buchwald- JACS, 2012, 12462
Sodeoka-TL, 2012, 5503Szabo-OL, 2012, 2882
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Three-component Oxytrifluoromethylation of Alkenes Mediated by Photoredox Catalysts
OIF3C
O
Togni' reagents
Buchwald- JACS, 2012, 12462
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Three-component Oxytrifluoromethylation of Alkenes Mediated by Photoredox Catalysts
S
CF3
Umemoto's reagents
BF4
Akita- ACIE 2012,9567
Linear alkene doesn’t react
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Oxytrifluoromethylation of unactivated double bonds
Akita- ACIE 2012,9567
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Kharasch–Sosnovsky