Nucleophilic trifluoromethoxylation of alkyl halides without silver

Fluorine-containing groups are widely used in pharmaceuticals, agrochemicals, and materials due to their unique electronic and lipophilic properties. The trifluoromethoxy (OCF₃) group, being strongly electron-withdrawing and highly lipophilic, is particularly valuable, but its direct installation remains difficult because the trifluoromethoxide anion is both poorly nucleophilic and unstable. Existing nucleophilic trifluoromethoxylations often require activated substrates (allylic, benzylic, or α-halo carbonyls) or silver-mediated conditions. The research question addressed here is whether a practical, silver-free, nucleophilic method can be developed to introduce OCF₃ into unactivated alkyl halides by generating CF₃O⁻ in situ under mild conditions. The study aims to create an easily prepared, stable reagent that releases CF₃O⁻ upon base activation, enabling broad-scope late-stage functionalization.

Prior strategies to synthesize trifluoromethyl ethers include indirect routes (nucleophilic fluorination of ether precursors and electrophilic trifluoromethylation of alcohols), which suffer from harsh conditions, toxicity, and limited scope. Direct strategies employ OCF₃-transfer reagents such as TFMT, DNTFB, TFBz, TASOCF₃, or AgOCF₃/CsOCF₃. Many of these require activation by fluoride (risking fluorination byproducts) or silver mediation and generally work best with activated electrophiles. Ritter used TASOCF₃ for aryl substrates with silver; Liu reported Pd-catalyzed aminotrifluoromethoxylation using AgOCF₃ or CsOCF₃; visible-light photocatalysis with N–OCF₃ reagents enables arene C–H trifluoromethoxylation. For unactivated alkyl halides, reported nucleophilic methods with TFMT, DNTFB, or TFBz gave very low yields (<10%) in the absence of silver. Only one example of benzyl chloride trifluoromethoxylation with AgOCF₃ afforded 29% yield, and no silver-free method for alkyl chlorides had been reported. These gaps motivate a reagent that can cleanly generate CF₃O⁻ without fluoride or silver.

Reagent design and preparation: (E)-O-trifluoromethyl-benzaldoximes (TFBO) were conceived to release CF₃O⁻ under basic conditions by elimination, inspired by base-promoted fragmentation of O-alkyl benzaldoximes. TFBO reagents were prepared from 2-(trifluoromethoxy)isoindoline-1,3-dione (PhthNOCF₃), water, HCl, and an aldehyde (1.5 equiv) at 80 °C overnight. Work-up: extract with CH₂Cl₂, dry (MgSO₄), concentrate, and purify by silica chromatography. The reagents are shelf-stable; an X-ray structure was obtained for 1d.

Reaction optimization: The model reaction used 5-iodopentyl 4-fluorobenzoate with TFBO in DMA under N₂. Base was essential; Cs₂CO₃ gave the highest yield. Other bases (Et₃N, DBU, KOtBu, CsF, Na₂CO₃, K₂CO₃) were inferior or ineffective. Substituent effects on TFBO showed 4-tert-butyl TFBO (1a) was optimal. Control reactions without base gave no product. 19F NMR monitoring of TFBO (1a) with Cs₂CO₃ detected CsOCF₃ (−20.9 ppm) and aryl nitrile, supporting in situ CF₃O⁻ generation. Optimized standard conditions: alkyl halide (1.0 equiv), TFBO 1a (5.0 equiv), Cs₂CO₃ (3.5 equiv) in DMA at 70 °C under N₂, overnight.

General product synthesis procedure: In an N₂ glovebox, combine alkyl halide (1.0 equiv), TFBO 1a (5.0 equiv) in DMA, add Cs₂CO₃ (3.5 equiv), and stir at 70 °C overnight. Cool to 50 °C, add NMO (2.0 equiv), stir 2 h, filter, concentrate, and purify (prep TLC). For some alkyl bromides/chlorides, modified conditions were used (e.g., higher temperature up to 90 °C, HMPA as cosolvent, and TBAI as additive; increased TFBO and Cs₂CO₃ loadings). Reactions were typically quantified by 19F NMR using benzotrifluoride as an internal standard.

Scope evaluation: A broad array of unactivated primary and secondary alkyl iodides, bromides, chlorides, and allyl/propargyl/benzyl halides were tested. Functional group tolerance included ester, ether, ketone, aldehyde, imide, amide, cyano, nitro, and aryl halides. Late-stage functionalization was demonstrated on complex molecules (e.g., derivatives of celecoxib, mycophenolic acid, D-biotin, idebenone, deoxycholic acid, ezetimibe, gibberellic acid, tadalafil, cyclosporin A, and pleuromutilin). Gram-scale synthesis was demonstrated for one example.

• A new class of trifluoromethoxylation reagents, (E)-O-trifluoromethyl-benzaldoximes (TFBO), was developed; they are readily prepared and thermally stable and release CF₃O⁻ upon base activation.
• Mechanistic probe: 19F NMR monitoring of TFBO 1a with Cs₂CO₃ showed formation of CsOCF₃ (−20.9 ppm) and aryl nitrile, confirming in situ CF₃O⁻ generation.
• Optimized standard conditions (DMA, 70 °C, N₂; TFBO 1a 5.0 equiv; Cs₂CO₃ 3.5 equiv) efficiently convert unactivated alkyl iodides to OCF₃ ethers with high yields: a representative set gave 49–98% yield (e.g., products 3–34; examples include 3: 92%, 5: 98%, 6: 91%, 12: 90%, 16: 95%, 21: 95%). Primary iodides generally gave higher yields than secondary iodides (31–34 lower, e.g., 31: 54%).
• Alkyl bromides and chlorides are also competent substrates under modified conditions (often higher temperature, HMPA, TBAI, and increased loadings): yields ranged from 30% to 97% (e.g., 3: 93% (Br), 71% (Cl); 16: 95% (Br), 69% (Cl); 35: 91% (Br), 70% (Cl); 39: 67% (Br), 30% (Cl)).
• Allylic, propargylic, and benzylic halides were successfully converted (35–39: up to 91% for Br and 70% for Cl cases).
• Chemoselectivity: selective conversion of alkyl iodides or bromides in the presence of alkyl chlorides was observed; alkyl chlorides remained intact under conditions that transform iodide/bromide.
• Functional group tolerance: ester, ether, ketone, aldehyde, imide, amide, cyano, nitro, and aryl halides are tolerated. Heteroaromatic substrates and amino acid derivatives are compatible. Alkyl OMs and OTs also serve as electrophiles.
• Low fluorination byproducts: fluorination side products were <10% in all cases examined.
• Stereochemical outcome: using a chiral secondary substrate (85% ee) gave product 33 with 8% ee, suggesting a significant SN1 contribution for secondary centers.
• Limitation: tertiary halides did not afford products. A gram-scale preparation of product 28 was achieved in 89% isolated yield, demonstrating scalability.

The work addresses the long-standing challenge of installing the OCF₃ group onto unactivated alkyl halides without reliance on silver salts or fluoride-mediated activation. TFBO reagents, readily assembled from aldehydes and PhthNOCF₃, provide a controlled in situ source of CF₃O⁻ under basic conditions, avoiding competing fluorination associated with fluoride activators and the cost/complexity of silver-mediated systems. The reaction proceeds under comparatively mild conditions (DMA, 70 °C, Cs₂CO₃) with broad substrate scope, good chemoselectivity for more reactive halides (I, Br) over chlorides, and tolerance of diverse functional groups, enabling late-stage diversification of complex molecules. The observed erosion of enantiopurity for a chiral secondary substrate and the lack of reactivity with tertiary halides are consistent with a mechanistic pathway that includes SN1-type character for more substituted systems. Collectively, the findings validate TFBO as a practical platform reagent for nucleophilic trifluoromethoxylation and open avenues for its application in medicinal and agrochemical synthesis.

(E)-O-trifluoromethyl-benzaldoximes (TFBO) function as efficient, silver-free nucleophilic trifluoromethoxylation reagents for alkyl halides. They are easily synthesized, shelf-stable, and activated by base to release CF₃O⁻, enabling broad-scope conversion of unactivated alkyl iodides, bromides, and chlorides under mild conditions with low fluorination byproducts. The method exhibits wide functional group tolerance, chemoselectivity, and applicability to late-stage modification of complex molecules, and is amenable to gram-scale synthesis. Future work could focus on expanding reactivity to tertiary substrates, improving enantiospecificity/retention for secondary centers, and developing catalytic or more atom-economical variants.

• No desired products were obtained with tertiary halides.
• Secondary alkyl halides generally gave lower yields than primary ones, and enantiopurity was not retained (e.g., 85% ee substrate gave 8% ee product), indicating potential SN1 pathways.
• For some alkyl bromides and chlorides, higher temperatures, specific additives (TBAI), and solvents (HMPA) as well as higher reagent/base loadings were required, reflecting reduced reactivity.
• Minor fluorination byproducts were observed, though typically <10%.