Reagent of the month – November - Langlois reagent

Trifluormehylation is an effective technique to increase drug candidate solubility and lipophilicity, and so strategies for adding the CF₃ group are being investigated. The Langlois reagent (sodium trifluormethylsulfinate) is a valuable reagent for radical trifluormethylation of a wide range of substrates. Bernard R. Langlois' group first developed methodology for radical trifluormethylation of arenes with optional Cu²⁺ catalysis in 1991 (https://doi.org/10.1016/0040-4039(91)80524-A), but since then, numerous trifluormethylation methods of other substrates have been developed (https://doi.org/10.1002/adsc.201400370).

Preparation of Langlois reagent

Langlois reagent can be prepared by elimination of trifluormethylsulfones such as I or II by sodium methoxide, or by reacting CF₃Cl with sodium dithionate (Na₂S₂O₄) (Figure 1).

Similarly, alternative perfluoralkylation agents can be synthesized utilizing other perfluoralkylsulfones. Perfluoralkylation processes of heteroarenes were successfully carried out using reagents such as C₂F₅SO₂Na, C₃F₇SO₂Na, C₆F₁₃SO₂Na or C₈F₁₇SO₂Na (https://doi.org/10.1002/adsc.201300199).

Applications in synthesis

When compared to other trifluormethylation agents such as electrophilic (CF₃⁺ producing) Togni's or Umemoto's reagents or nucleophilic reagents such as Ruppert's reagent (CF₃SiMe₃), Langlois reagent has a wider substrate scope due to its nucleophilic or electrophilic character.

In the presence of an oxidant such as AgOTf, tertbutylhydroperoxide (TBHP), or Mn(OAc)₃, trifluormethanesulfinate produces a CF₃ radical, which can be used for addition or substitution reactions on aryl or vinylboronic acids and potassium organotrifluorborates (Figure 2) (https://doi.org/10.1021/ol3022726, https://doi.org/10.1039/C2CC36554E, https://doi.org/10.1021/jo4023233), arenes and alkenes (Figure 3) (https://doi.org/10.1039/C3CC41667D, https://doi.org/10.1002/anie.201303576).

Oxotrifluormethylation of alkenes can be done under oxidative circumstances, but a superior photochemical technique for hydrotrifluormethylation was devised in 2013 (Figure 4) (https://doi.org/10.1039/C3SC51209F).

Langlois reagent in drug synthesis

Phil S. Baran's group described direct C-H trifluormethylation of deoxyuridine with Langlois reagent in 2011 (10.1073/pnas.1109059108), providing Trifluridine - an antiviral drug against herpes virus in a moderate yield in aqueous solution, making it possible to produce this drug using greener chemistry (Figure 5).