A scalable and operationally simple radical trifluoromethylation

Abstract

The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge. Current state-of-the-art reagents for appending the CF3 functionality directly are highly effective; however, their use on preparative scale has minimal precedent because they require multistep synthesis for their preparation, and/or are prohibitively expensive for large-scale application. For a scalable trifluoromethylation methodology, trifluoroacetic acid and its anhydride represent an attractive solution in terms of cost and availability; however, because of the exceedingly high oxidation potential of trifluoroacetate, previous endeavours to use this material as a CF3 source have required the use of highly forcing conditions. Here we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to affect a facile decarboxylation to the CF3 radical.

Figure 1. Design principles for a mild photochemical decarboxylation of trifluoroacetate.

(a) TFA and TFAA are desirable CF₃ sources from the perspective of availability and cost, but have traditionally proven challenging to utilize. (b) Strategic electrochemical tuning using the sacrificial redox auxiliary pyridine N-oxide allows for reductive decarboxylation within the electrochemical window of tris(bipyridine)ruthenium(II). The reagent undergoes irreversible reduction (determined with differential pulse voltammetry, E_1/2^red=−1.10 V versus SCE in MeCN, Supplementary Figs 1 and 2) with onset reduction observable at −0.86 V versus SCE.

Figure 2. Scalable radical trifluoromethylation of arenes, heteroarenes and alkenes with trifluoroacetic anhydride.

(a) A variety of electron-rich and electron-neutral substrates are amenable to trifluoromethylation. (b) Substrates with functionality for cross-coupling were compatible with the reaction conditions. (c) Radical trifluoromethylation of alkenes. (d) Products 17–20 were obtained from reactions run on 5 g scale using 0.1 mol% Ru(bpy)₃Cl₂. Isolated yields are indicated below each entry, except in the case of volatile compounds (¹⁹F NMR yields) and represent a single experiment. See Supplementary Methods for experimental details. *Position of functionalization on the minor regioisomeric product. ¶10 equiv. benzene. #Position of functionalization on the minor doubly functionalized product. §4 equiv. of pyridine N-oxide and 8 equiv. of TFAA, 24 h. †Run in CH₂Cl₂, stirred with methanol on reaction completion. ‡Run in CH₂Cl₂, stirred with DBU on reaction completion. §§3 equiv. of pyridine N-oxide and 3.1 equiv. of TFAA. Ru(bpy)₃Cl₂, tris(bipyridine)ruthenium(II) chloride; TFAA, trifluoroacetic anhydride; MeCN, acetonitrile; Me, methyl; Boc, tert-butyloxycarbonyl; Ph, phenyl; Ts, para-toluenesulfonyl.

Figure 3. Synthetic utility of the trifluoromethylation procedure.

(a) Trifluoromethylation of cross-coupling precursors. (b) Trifluoromethylation followed by cross-coupling leads to the production of specialty scaffolds. (c) Synthesis of 3-(trifluoromethyl)pyridine derivatives can be accomplished through pyridone functionalization. Boc, tert-butyloxycarbonyl; SPhos, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; BMIDA, boronic acid methyliminodiacetic acid ester. Yields represent a single experiment.

Figure 4. Scalable trifluoromethylation of N-Boc-pyrrole in batch and flow.

(a) An 18.3-g reaction in batch provides 17.8 g of product (57%) in 15 h. Improved yields were obtained when the reaction was run at a steady state in flow, with a 71% yield of isolated material from 20 g of starting material. (b) The reaction can be run on 100 g scale for <$150 total reagent and catalyst cost calculated using academic vendor pricing. #Position of functionalization on the minor doubly functionalized product. Yields represent a single experiment. Boc, tert-butyloxycarbonyl.