application-elemental-lanthanides-selective-c-f-activation

Application of Elemental Lanthanides in the Selective C-F Activation of Trifluoromethylated Benzofulvenes Providing Access to Various Difluoroalkenes

The selective activation of one carbon-fluorine bond in polyfluorinated aromatic molecules or in trifluoromethyl-containing substrates offers the ...

Université de Reims Champagne Ardenne

The interactions of three bis(amide) ligands derived from tartaric acid with copper (II) were investigated in aqueous solution by a combination of potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance (EPR), and mass spectrometry. The formation constants of the complexes were measured and their relative structures were reported. The sites of complexation of these ligands are investigated based mostly on their electronic and EPR spectra and on the comparison with the behaviour of some analog compounds.

Thermodynamic and spectroscopic studies of copper (II) complexes with three bis(amide) ligands derived from L-tartaric acid.

The diastereoselective nucleophilic trifluoromethylation of a range of ketoamides derived from L-tartaric acid has been studied. TMSCF3 in the presence of a catalytic amount of K2CO3 in DMF has been identified as the conditions leading to the highest diastereoselectivities. A sequential one-pot reaction trifluoromethylation-etherification of the trifluoromethylcarbinol has been developed. Only one further one-pot reaction, ketal hydrolysis-oxidative cleavage, led to the final alpha-trifluoromethylated alpha-alkoxyaldehydes. This procedure was applied to the preparation of a series of enantiopure aryl, heteroaryl, and alkyl alpha-trifluoromethyl-alpha-alkoxyaldehydes.

Enantiopure quaternary alpha-trifluoromethyl-alpha-alkoxyaldehydes from L-tartaric acid derived ketoamides.

The diketone 2-fluoro-2-(trifluoromethyl)-1-phenylhexane-1,5-dione 3 was synthesized by a Mukaiyama Michael type reaction from the corresponding tetrafluoroenol silyl ether prepared from pentafluoropropiophenone. This diketone was treated under basic conditions and was converted, depending on the stoichiometry of the base, into the surprisingly stable ketol 4-fluoro-4-(trifluoromethyl)-3-hydroxy-3-phenylcyclohexanone 4 as a single diastereomer (catalytic KOH) or to the biphenylol 6-(trifluoromethyl)biphenyl-3-ol (excess KOH, THF) 5. Solvolysis of the trifluoromethyl group (anionic activation) occurred using excess KOH in alcohol. The corresponding cyclohexenone derivative 7, the usual product of Robinson annulation, might be prepared in good yield via mesylation of the ketol. Thus various unprecedented fluorinated cyclohexane and aromatic derivatives were achieved in a few steps from the commercially available pentafluoropropiophenone.

Synthesis of trifluoromethyl cyclohexyl, cyclohexenyl and aryl compounds via stepwise Robinson annulation.

The addition of trifluoromethyl(trimethyl)silane (TFMTMS) to tartaric acid derived aromatic 1,4-diketones was reported to be highly stereoselective but also chemoselective towards a monoaddition product. This chemoselectivity remained unexplained. Complementary experiments and monitoring of the reaction by electrospray ionization mass spectrometry (ESI-MS) show that: i) the countercation (tetrabutylammonium (TBA(+)) or Cs(+)) associated to the initiator and the charged intermediates in the chain reaction plays a crucial role and ii) in the case of a tetrabutylammonium salt initiator, the second addition on the preformed monoadduct does occur but the resulting bis(trifluoromethyl)carbinolate is unable to evolve through the chain-transfer process and it exhibits an intramolecular Si-O interaction.

The role of the counterion and of silicon chelation in the selective mono(trifluoromethylation) of tartaric acid derived 1,4-diketones.

Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl has been employed for selective single C-F activation in benzofulvenes comprising an exocyclic CF substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds.

Generation of ϵ,ϵ-Difluorinated Metal-Pentadienyl Species through Lanthanide-Mediated C-F Activation.

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1',2')-dihydroxyethyl substituent of homoDMDP with -CF proved detrimental for enzyme binding, introduction of a -CF moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast.

Article	Year
Thermodynamic and spectroscopic studies of copper (II) complexes with three bis(amide) ligands derived from L-tartaric acid. Journal of inorganic biochemistry\| PubMed ID: 16271395	2005
Enantiopure quaternary alpha-trifluoromethyl-alpha-alkoxyaldehydes from L-tartaric acid derived ketoamides. The Journal of organic chemistry\| PubMed ID: 18816141	2008
Synthesis of trifluoromethyl cyclohexyl, cyclohexenyl and aryl compounds via stepwise Robinson annulation. Organic & biomolecular chemistry\| PubMed ID: 21049103	2011
The role of the counterion and of silicon chelation in the selective mono(trifluoromethylation) of tartaric acid derived 1,4-diketones. Chemistry (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 21837729	2011
Generation of ϵ,ϵ-Difluorinated Metal-Pentadienyl Species through Lanthanide-Mediated C-F Activation. Chemistry (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 28980352	2017
Synthesis and glycosidase inhibition potency of all-trans substituted 1-C-perfluoroalkyl iminosugars. Carbohydrate research\| PubMed ID: 29777947	2018

Fabien Massicot

Biography

JoVE Journal Publications

Other Publications