Fluoroalkylation: Expansion of Togni Reagents

The installation of highly fluorinated groups into drug and pesticide candidates is a powerful strategy to modulate their properties. An incorporated fluorinated sidechain can tune the acidobasic behavior and lipophilicity, impart a dipole moment, lock confirmation, mitigate undesirable metabolic degradation of the parent compound. Fluorinated groups have been typically limited to a single fluorine or trifluoromethyl groups due to synthetic access. More elaborate fluoroalkylation is now possible with the development of a new suite of reagents including hypervalent iodine perfluoroalkylation reagents as well as fluoroalkyl bromides, silanes, carboxylates, and sulfonyl fluorides that allow late stage fluoroalkylation of a variety of functional groups through different reactivities.

Hypervalent iodine reagents

The Togni reagents have over the last decade become a standard tool that provides expedient access to trifluoromethylated compounds important for drug and pesticide discovery programs.1 These hypervalent iodine compounds are electrophilic CF3-transfer reagents for direct, mild, and efficient trifluoromethylation and in many cases operate via trifluoromethyl radicals as the key reactive intermediates.

More recently, other cyclic hypervalent iodine reagents with increased hydrolytical and thermal stability have been developed as mild and conveniently handled electrophilic chlorination, fluorination and azidations reagents. The shelf-stable fluoroiodane reagent allows to perform elegant fluorinative functionalizations and fluorocyclizations of olefins under mild conditions, while the azidoiodane reagent can be used to as a formally electrophilic azidation reagent for azidation of enolates.

hypervalentiodine1
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Togni perfluoroalkyl reagents

3-analogues, many types of transformations that work well with CF3-Togni reagents can be done with these reagents as well, providing access to rare and potentially attractive fluorinated chemical space.2

With a set of “extended Togni reagents” in hand, the lead compound can be diversified in the last stage of the synthesis to afford the hard-to-access fluoroalkyl-decorated derivatives.

perfluoroalkyl1

2CF2— “extended Togni reagents” engage in a radical cyclization reaction with olefins and acetylenes giving access to rare tetrafluorinated heterocycles.3 The incorporation of a —CF2CF2— moiety into a cyclic structure imparts the molecule a unique combination of properties called “polar hydrophobicity” – a permanent dipole combined with the solvophobic behaviour of the tetrafluoroethylene unit.

bromides
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Fluoroalkyl bromides

Substituted fluoroalkyl bromides turn into powerful nucleophilic fluoroalkylation reagents after being metallated with isopropylmagnesium chloride-lithium chloride complex (Turbo-Grignard).4 The in-situ generated fluoroalkylmagnesium chloride intermediate is moderately stable up to -40 °C and can be efficiently trapped with various electrophiles to afford the —CF2CF2— linked products.

bromidereal
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Fluoroalkyl silanes

Substituted fluoroalkyl silanes serve as traditional nucleophilic sources of the fluoroalkyl synthon. Upon activation with catalytic fluoride or alkoxide, they can fluoroalkylate a range of aldehydes, reactive ketones or iminiums. The silanes can also engage in transition-metal catalyzed formation of R-CF2CF2- substituted aromatics.

salines
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Tetrafluoropropionates

β-Substituted cesium tetrafluoropropionates are convenient starting materials for the construction of fluoroalkyl carboxamides. The pKa values of such amide groups are significantly lower than their non-fluorinated counterparts, offering potential to modulate the behaviour of drug candidates. The cesium salts can be easily handled in air due to their reduced hygroscopicity compared to the highly hygroscopic free carboxylic acids.

propionates
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Fluoroalkylsulfonyl fluorides

Fluoroalkylsulfonyl fluorides can be used as moderately reactive electrophilic fluoroalkylsulfonylation reagents. Whereas the related fluoroalkylsulfonyl chlorides can also behave as electrophilic chlorination reagents towards amines affording undesirable N-chloroamines, the fluoroalkylsulfonyl fluorides give slower, yet very clean nitrogen sulfonylation to give the corresponding sulfonamides. Fluoroalkylsulfonylation of the amine nitrogen greatly lowers the pKa value of NH group and can be used to modulate the behaviour of the drug candidate or build additional molecular complexity around the highly acidic fluoroalkylsulfonamide nitrogen.

sulfonylfluorides
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Special thanks to CF Plus Chemicals for contributing this Technology Spotlight!

References

1.
Charpentier J, Früh N, Togni A. 2015. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem. Rev.. 115(2):650-682. http://dx.doi.org/10.1021/cr500223h
2.
Matoušek V, Václavík J, Hájek P, Charpentier J, Blastik ZE, Pietrasiak E, Budinská A, Togni A, Beier P. 2016. Expanding the Scope of Hypervalent Iodine Reagents for Perfluoroalkylation: From Trifluoromethyl to Functionalized Perfluoroethyl. Chem. Eur. J.. 22(1):417-424. http://dx.doi.org/10.1002/chem.201503531
3.
Charpentier J, Früh N, Foser S, Togni A. 2016. Tandem Radical Fluoroalkylation?Cyclization: Synthesis of Tetrafluoro Imidazopyridines. Org. Lett.. 18(4):756-759. http://dx.doi.org/10.1021/acs.orglett.6b00018
4.
Budinská A, Václavík J, Matou?ek V, Beier P. 2016. Nucleophilic Tetrafluoroethylation Employing in Situ Formed Organomagnesium Reagents. Org. Lett.. 18(22):5844-5847. http://dx.doi.org/10.1021/acs.orglett.6b02890

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