Isolation and Reactivity of Trifluoromethyl Iodonium Salts

Abstract

The strategic incorporation of the trifluoromethyl (CF3) functionality within therapeutic or agrochemical agents is a proven strategy for altering their associated physicochemical properties (e.g., metabolic stability, lipophilicity, and bioavailability). Electrophilic trifluoromethylation has emerged as an important methodology for installing the CF3 moiety onto an array of molecular architectures, and, in particular, CF3 λ(3)-iodanes have garnered significant interest because of their unique reactivity and ease of handling. Trifluoromethylations mediated by these hypervalent iodine reagents often require activation through an exogenous Lewis or Brønsted acid; thus, putative intermediates invoked in these transformations are cationic CF3 iodoniums. These iodoniums have, thus far, eluded isolation and investigation of their innate reactivity (which has encouraged speculation that such species cannot be accessed). A more complete understanding of the mechanistic relevance of CF3 iodoniums is paramount for the development of new trifluoromethylative strategies involving λ(3)-iodanes. Here, we demonstrate that CF3 iodonium salts are readily prepared from common λ(3)-iodane precursors and exhibit remarkable persistence under ambient conditions. These reagents are competent electrophiles for a variety of trifluoromethylation reactions, and their reactivity is reminiscent of that observed when CF3 iodanes are activated using Lewis acids. As such, our results suggest the mechanistic relevance of CF3 iodonium intermediates in trifluoromethylative processes mediated by λ(3)-iodanes. The isolation of CF3 iodonium salts also presents the unique opportunity to employ them more generally as mechanistic probes.

Figure 1

Representative CF₃-containing therapeutic and agrochemical compounds.

Figure 2

Trifluoromethylations involving hypervalent iodine reagents and proposed reactive intermediates. (A) Conventional λ³-iodanes for electrophilic trifluoromethylation. (B) General mechanism for trifluoromethylation of a nucleophile under Lewis acid catalysis. The activated iodane is highlighted in red. (C) Structural distinctions between proposed intermediates in λ³-iodane mediated trifluoromethylations. (D) Experimental evidence suggests the predominance of iodane character for 1 and 2 under Lewis or Brønsted acid activation.

Scheme 1. Attempted Syntheses of CF₃ Iodoniums That Have Previously Been Reported

Figure 3

Synthesis of (A) 1·HCl and (B) 2·HCl by reacting their parent iodanes with HCl (g). (C) The chloride counterion proved paramount for successful iodonium synthesis, as the remaining halide series proved ineffectual for stabilizing the nascent iodonium. (D) Anion metathesis of 1·HCl with NaBArF₂₄ afforded the corresponding salt, 1·HBArF₂₄. (E) Anion metathesis of 1·HCl with NaOTf affords the unstable salt 1·HOTf, which subsequently decomposes via reductive elimination. One decomposition product was identified as 1·HBF₄, and the X-ray structure of 1·HBF₄ (thermal ellipsoids at 50% probability) is shown [atom code: green (F); red (O); pink (B); violet (I)]. Only one of the two inequivalent molecules of 1·HBF₄ is shown. Hydrogen atoms other than the O–H atom have been omitted for clarity.

Figure 4

(A) The solid-state structure of 1·HCl (thermal ellipsoids at 50% probability). While the hydroxyl hydrogen atom is shown, all others have been removed for clarity. Atom code: green (F); red (O); violet (I); yellow (Cl). (B) Halide bridging interaction between one molecule of 1·HCl in the asymmetric unit and a symmetry generated partner. (C) The solid-state structure of 11 (thermal ellipsoids at 50% probability). Hydrogen atoms have been removed for clarity. Atom code: green (F); violet (I); yellow (Cl); beige (Si).

Scheme 2. (Top) Synthesis of 1·AcCl by Dissolution of 1·HCl in Neat Acetyl Chloride at Room Temperature. (Bottom) Synthesis of 2·MeCl under Vilsmeier–Haack Conditions

The solid-state structure of 1·AcCl is also shown (thermal ellipsoids at 50% probability). Hydrogen atoms are omitted for clarity. Atom code: green (F); red (O); violet (I); yellow (Cl). Note: The acyl chloride intermediate is directly esterified without isolation. The solid-state structure of 2·MeCl is also shown (thermal ellipsoids at 50% probability). Hydrogen atoms are omitted for clarity. Atom code: green (F); red (O); violet (I); yellow (Cl).

Figure 5

Solid-state structure of 2·HCl. (Left) One of the four inequivalent molecules in the asymmetric unit (thermal ellipsoids at 50% probability). While the carboxylic acid hydrogen atom is shown, the remaining hydrogen atoms are omitted for clarity. Cocrystallized MeCN has also been omitted for clarity. Atom code: green (F); red (O); violet (I); yellow (Cl). (Right) The asymmetric unit observed for crystalline 2·HCl (thermal ellipsoids at 50% probability). Hydrogen atoms and MeCN solvent molecules omitted for clarity.

Figure 6

Electronic structure calculations showing the frontier molecular orbitals of (A) 1 and 1·HCl and (B) 2 and 2·HCl [DFT; B3LYP; 6-311+G(d,p)].

Scheme 3. Oxidation of Au(I) and Fe(II) Complexes by CF₃ Iodoniums

General conditions: iodonium (1.0–3.0 equiv) and metal complex (1.0 equiv) were combined at room temperature and stirred (2–20 min). See the Supporting Information for complete details.

Scheme 4. Reactions of CF₃ Iodoniums with Azole (A, B), Indole (C), Olefinic (D), Enolate (E), Phosphate (F), Sulfide (G), and Sulfonate (H) Nucleophiles

General conditions: iodonium (1.0 equiv), substrate (1.0–3.0 equiv), and NaBArF₂₄ (0.0–0.1 equiv) were combined and stirred at an appropriate temperature (room temperature to 60 °C; 2–16 h). See the Supporting Information for complete details.