O-Trifluoromethylation of ketones: an alternative straightforward route to alkenyl trifluoromethyl ethers

Abstract

Here we report an unprecedented O-trifluoromethylation of ketones using chloro(phenyl)trifluoromethyl-λ³-iodane (CPTFI). Our method provides a new strategy for the facile synthesis of various synthetically valuable alkenyl trifluoromethyl ethers, particularly those CF₃O-substituted terminal alkenes and cyclic alkenes that have been elusive until now, from simple aromatic, aliphatic, and cyclic ketones. The success of this reaction is attributed to the full utilization of the multifunctionality of CPTFI: (1) its strong Lewis acid activation ability, which enables weak nucleophiles such as Cl anions to attack the carbonyl group; (2) its bifunctionality, which allows for the introduction of CF₃ and Cl into the carbonyl group in one step, thus enabling the obtainment of alkenyl trifluoromethyl ethers by further removal of HCl. The further transformation in the synthesis of CF₃O-cyclopropanes, which were previously largely unexplored, reveals the significant potential of alkenyl trifluoromethyl ethers as valuable CF₃O-containing building blocks in the discovery of innovative materials, pharmaceuticals, and agrochemicals.

Fig. 1. (A) Overview of the strategies for construction of the CF₃O group. (B) Challenge of O-trifluoromethylation of ketones.

Fig. 2. (A) Importance of the alkenyl (fluoroalkyl) ether motif. (B) Current limited straightforward approaches to alkenyl trifluoromethyl ethers. (C) This work.

Fig. 3. (A) Reaction design. (B) Experimental results of the formation of 2a. (C) DFT calculated LUMO energies (eV) for PhI(CF₃)-X.

Fig. 4. Scope of ketones. Unless otherwise noted, the standard conditions were as follows: 1 (2 equiv.), CPTFI (0.2 mmol, 1 equiv.), AlCl₃ (25 mol%), CH₂Cl₂ (0.5 mL), 80 °C, 1 h. ¹⁹F NMR yield using α,α,α-trifluorotoluene (PhCF₃) as an internal standard. ¹⁹F NMR yields of 3 are in green. Isolated yields are given in parentheses. ^aAlCl₃ (50 mol%), CH₂Cl₂ (0.1 mL), 10 h. ^bCH₂Cl₂ (0.1 mL), 2 h. ^cCH₂Cl₂ (0.3 mL), 1.5 h. ^dCH₂Cl₂ (0.1 mL). ^eCH₂Cl₂ (0.3 mL), 2 h. ^fCH₂Cl₂ (0.1 mL), 10 h. ^gCH₂Cl₂ (0.1 mL), 5 h. ^hCH₂Cl₂ (1 mL), 1 h, then adding KOH (20 equiv.), MeOH (3 mL), 50 °C, 10 h.

Fig. 5. (A) Monitoring the reaction process. (B) Study on the conversion of crude isolated 3 to 2 w/o AlCl₃. (C) Proposed mechanism.

Fig. 6. (A) 10 mmol scale synthesis of 2a. Conditions: 1a (2 eq.), CPTFI (10 mmol, 1 eq.), AlCl₃ (25 mol%), CH₂Cl₂ (25 mL), 80 °C, 1 h. (B) Synthesis of CF₃O-cyclopropanes using alkenyl trifluoromethyl ethers as CF₃O-building blocks with various carbene precursors. Conditions: ^a2a (0.1 mmol), tosylhydrazone (2 eq.), K₂CO₃ (3 eq.), FeTPPCl (3 mol%), toluene (1 mL), 80 °C, N₂, 2 h. ^b2a (0.1 mmol, 1 eq.), ethyl diazoacetate (3 eq.), fac-Ir(dFppy)₃ (2 mol%), MeCN (1 mL), 18w blue LEDs, rt, N₂, 48 h. ^c2a (0.1 mmol, 1 eq.), TMSCF₂Br (3 eq.), TBAB (6 mol%), toluene (1 mL), 110 °C, 4 h. ^d2a (0.1 mmol, 1 eq.), KO^tBu (12 eq.), CHCl₃ (12 eq.), CH₂Cl₂ (0.5 mL), −45 to 110 °C, 1 h. Diastereomeric ratio (d.r.) determined by ¹⁹F NMR. ^e2a (0.1 mmol), BzOCH₂I (3 eq.), Zn (3 eq.), FeTPPCl (3 mol%), THF (1 mL), 60 °C, N₂, 4 h. (C) One-pot synthesis of CF₃O-cyclopropane from ketone. Conditions: CPTFI (0.2 mmol, 1 eq.), 1a (2 eq.), AlCl₃ (25 mol%), CH₂Cl₂ (0.5 mL), 80 °C, 1 h, then tosylhydrazone (2 eq.), K₂CO₃ (3 eq.), FeTPPCl (3 mol%), toluene (1 mL), 80 °C, N₂, 2 h. (D) Application in the synthesis of drug analogues.