Redox-Neutral TEMPO Catalysis Toward Direct Radical (Hetero)Aryl C–H Di- and Trifluoromethoxylation

Abstract

Applications of TEMPO^• catalysis for the development of redox-neutral transformations are rare. Herein, we report the first TEMPO^•-catalyzed, redox-neutral C–H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional group tolerance, and can be employed for the late-stage functionalization of complex drug-like molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV-Vis studies, and DFT calculations support the proposed oxidative TEMPO^•/TEMPO⁺ redox catalytic cycle. Mechanistic studies also suggest that Li₂CO₃ plays an important role in preventing catalyst deactivation. These findings will provide new insight into the design and development of novel reactions through redox-neutral TEMPO^• catalysis.

Graphical Abstract

TEMPO-catalyzed redox-neutral di- and trifluoromethoxylation of arenes and heteroarenes. The strategy exhibits high functional group tolerance and offers flexible late-stage functionalization of drug-like molecules. Mechanistic studies suggest an oxidative TEMPO^•/TEMPO⁺ redox catalytic cycle and that Li₂CO₃ plays an important role in preventing catalyst deactivation.

TEMPO^• (2,2,6,6-tetramethylpiperidine 1-oxyl radical) and its derivatives have a rich history in the fields of biochemistry, materials science, and organic chemistry.^[1] These open-shell species have diverse reactivity and can undergo reactions such as a single-electron transfer (SET) process to access three discrete oxidation states (i.e., TEMPO^–/TEMPO^•/TEMPO⁺) or abstract hydrogen atoms from C–H/X–H bonds.^[2] Their unique redox properties and chemical reactivity render TEMPO^• and related aminoxyl radicals a versatile class of radical reagents to achieve one/two-electron oxidation,^[3] hydrogen atom transfer (HAT),^[4] proton-coupled electron transfer (PCET),^[5] or radical trapping reactions.^[6] The majority of these transformations, however, require either a stoichiometric amount of aminoxyl radicals or the addition of external oxidants such as hypochlorite, silver, or molecular oxygen (O₂) to recycle aminoxyl radicals.^[7] In lieu of common external oxidants, elegant aminoxyl radical-catalyzed reactions driven by electrooxidation have been recently reported by Lei,^[8] Lin,^[9] Minteer,^[10] Stahl,^[11] and others.^[12]

Despite recent advances, applications of aminoxyl radical catalysis for the development of redox-neutral transformations^[13] without the aid of an external oxidant or electrooxidation are rare. Baran et al. reported a seminal TEMPO^•-mediated intramolecular, redox-neutral, radical alkane desaturation reaction.^[14] Although they tested the catalytic activity of TEMPO^•, they pointed out that its low turnover number (TON ≤ 3) renders the catalytic reaction inefficient. To date, efficient redox-neutral TEMPO^• catalysis that proceeds through a TEMPO^•/TEMPO⁺ redox cycle remains elusive. The successful development of such a catalytic platform could expand the reactivity profile of the aminoxyl radical’s redox chemistry and advance fundamental knowledge in radical chemistry.

In our quest for the establishment of redox-neutral TEMPO^• catalysis, we focused our attention on the development of unprecedented TEMPO^•-catalyzed intermolecular, redox-neutral (hetero)aryl C–H functionalization. Herein, we report the first success in this area, describe the experimental and computational studies that support the TEMPO^•/TEMPO⁺ redox cycle, and outline a new approach for the preparation of di- and trifluoromethoxylated (hetero)arenes (Figure 1). We looked to highly sought-after di- and trifluoromethoxylated (hetero)arenes^[15] as synthetic targets because of the unique structural^[16] and electronic properties^[17] that make them an important group of ethers in the pharmaceutical, agrochemical, and materials sciences.^[15a-c] Recently, we and others reported the synthesis of di- and/or trifluoromethoxylated (hetero)arenes by employing visible-light photoredox catalysts,^[18] transition metals,^[18f] and/or stoichiometric oxidants/activators.^[19] However, utilizing TEMPO^• as a catalyst for synthesis offers an attractive alternative due to its low cost,^[20] environmental friendliness,^[21] and thermodynamic^[22] and kinetic stability.^[23] Also, our findings could provide new insight into the design and development of new reactions through redox-neutral TEMPO^• catalysis.

Figure 1.

TEMPO^•-Catalyzed redox-neutral aryl C-H functionalization.

The mechanistic hypothesis of the proposed transformation is outlined in Scheme 1. We envisioned that the reaction proceeds through an oxidative redox cycle beginning SET between di- or trifluoromethoxylating reagent 1a (E_p = +0.11 V vs SCE)^[18g] or 1b (E_p = +0.14 V vs SCE)^[18e] and TEMPO^• (E_1/2 = +0.62 V vs SCE),^[12b] generating 2,2,6,6-tetramethyl-1-oxo-1λ⁴-piperidine (TEMPO⁺) and the di- or trifluoromethoxy radical (^•OR_F). Although the SET operates against a moderate potential gradient of approximately +0.5 V, such a redox process is possible if the onward reaction following the electron transfer is irreversible.^[24] Addition of ^•OR_F to an arene forms cyclohexadienyl radical Id (E_1/2 = −0.10 V vs. SCE),^[25] which is then oxidized by TEMPO⁺, regenerating the TEMPO^• catalyst and delivering cyclohexadienyl cation Ie. Rearomatization of Ie via deprotonation should be highly favored, affording the desired product If.

Scheme 1.

Proposed mechanism for the TEMPO^•-catalyzed di- and trifluoromethoxylation of (hetero)arenes.

We tested our hypothesis and obtained the desired difluoromethoxylated product (3a) in 83% yield when a mixture of benzene (2a), difluoromethoxylating reagent (1a), Li₂CO₃, and TEMPO^• (5 mol%) was heated at 60 °C for 20 hours (Table 1, entry 1). Control experiments indicated that both TEMPO^• and Li₂CO₃ are critical. The absence of either one of these components led to either no desired reaction or low yield (entries 2 and 3). Mechanistic studies suggested that Li₂CO₃ prevents catalyst deactivation (vide infra). Replacement of Li₂CO₃ with more soluble bases such as Cs₂CO₃ or 2,6-di-^tBu-4-me-pyridine resulted in reagent decomposition, decreasing the yields to 29% and 39%, respectively (entries 4 and 5). When we conducted the reaction at room temperature or under diluted conditions (0.10 M), we obtained lower yields of 50% and 49%, respectively (entries 6 and 7). The use of a MeCN/DCE solvent mixture (1:1) is essential as the absence of either solvent led to poor yields (entries 8 and 9). Presumably, the partial solubility of reagent 1a in the solvent mixture allows the slow introduction of 1a and so maintains its integrity. While using 1 equivalent of benzene afforded the product in a lower yield, the reaction proceeded with similar efficiency in the presence of water or air (entries 10–12).

Table 1.

Deviation from the Optimized Conditions^a

^aReactions were performed using 1 equivalent of reagent and 10 equivalents of benzene.

^bYields were determined by ¹⁹F NMR spectroscopy using trifluorotoluene as an internal standard. RSM = remaining starting material (1a).

Having identified the optimal reaction conditions, we explored the scope of TEMPO^•-catalyzed redox-neutral (hetero)aryl C–H difluoromethoxylation (Table 2a). We found that this protocol has a broad substrate scope and high functional group compatibility. For example, the reaction tolerated halide substituents (3b, 3c, 3g, 3r), which provide useful handles for further structural elaborations through metal-catalyzed coupling reactions. Notably, substrates containing benzylic C–H bonds (3d, 3e, 3f, 3g), which are often sites for undesired reactivity in radical processes, were compatible and afforded the desired products in good yields.^[26] Arenes with other functional groups, including unprotected phenol (3i, 3j, 3k), alkene (3j), cyano (3i), nitro (3j), aldehyde (3k), ketone (3l, 3m), ester (3o), sulfone (3p), and carbonate (3p), were viable substrates as well. Importantly, our protocol is amenable for late-stage difluoromethoxylation reactions of medicinally relevant molecules using one equivalent of substrates such as Leflunomide^® (antirheumatic drug, 3s), Efavirenz^® (antiretroviral drug for treating HIV, 3t), and derivatives of Diacetonefructose (3u), Benzocaine^® (pain killer, 3v), and trans-Androsterone (3w).

Table 2.

Selected Examples of Di- and Trifluoromethoxylation of (Hetero)Arenes.

^aReactions were performed using 1 equivalent of reagent 1a or 1b and 10 equivalents of (hetero)arene. The asterisk (*) denotes the functionalization of minor regioisomeric products. Due to the high volatility of the products, overall yields and the ratio of the constitutional isomers were determined by ¹⁹F NMR spectroscopy using trifluorotoluene as an internal standard.

^bReactions were performed with 10.0 mol% of TEMPO.

^cReactions were performed with 20 mol% of TEMPO.

^dReactions were performed using 2.00 equivalents of reagent 1a, 1.0 equivalent of (hetero)arene and 50 mol% TEMPO^• in MeCN:DCE 1:1 (0.200 M).

^eOverall yields were determined based on the recovered starting material. ^fIsolated yield.

To further demonstrate the synthetic utility of redox-neutral TEMPO^• catalysis, we successfully achieved radical trifluoromethoxylation of a broad range of (hetero)arenes using trifluoromethoxylating reagent 1b (Table 2b). Again, the reaction tolerated a wide array of functionalities such as benzylic C–H bond (4c), carbonyl and cyano (4c-4g, 4l), phosphine oxide (4h), sulfone (4i), carbonate (4j) and imide (4k) groups. The selectivity of the TEMPO^•-catalyzed (hetero)aryl C–H di- and trifluoromethoxylation reactions is governed by the radical nature of the process, which provides rapid access to multiple regioisomeric products without labor-intensive, parallel multistep analog synthesis,^[27] conveniently generating promising new candidates that might have never been evaluated otherwise.

Our mechanistic hypothesis for the TEMPO^•-catalyzed redox-neutral reaction depicted in Scheme 1 is supported by kinetic measurements, catalytic intermediate isolation and resubjection, UV-Vis studies, EPR measurements, and DFT calculations. The intermolecular kinetic isotope effect (KIE) of the difluoromethoxylation reaction using equimolar amounts of benzene and benzene-d₆ was found to be 1, implying that the cleavage of the aryl C–H takes place after the rate-determining step (Figure 2a). Kinetic studies using Burés’ method^[28] suggested a first-order dependence on TEMPO^• (Figure S3). To understand the role of the TEMPO^• catalyst, we synthesized and compared the catalytic activity of TEMPO⁺ and TEMPO^– with TEMPO^• under standard reaction conditions (Figure 2b).^[29] In the presence of Li₂CO₃, while TEMPO^– failed to promote the reaction, TEMPO^• and TEMPO⁺ afforded the desired product in 83% and 51% yield, respectively. In the absence of Li₂CO₃, the reactivity dropped dramatically in all cases, and only 3% of product 3a was obtained using TEMPO^•. These data showed that (i) Li₂CO₃ is critical for catalytic activity, (ii) TEMPO^– is catalytically inactive, and (iii) TEMPO^• and TEMPO⁺ are catalytically active only in the presence of Li₂CO₃. Given that our di- and trifluoromethoxylation reactions generate one equivalent of acid and that acid can promote disproportionation of TEMPO^• (K = 3.3 × 10⁴ M⁻²) to produce catalytically inactive TEMPO⁺ and TEMPOH₂⁺ species,^[30] it may explain the lack of catalytic turnover of TEMPO^• in the absence of base. UV-Vis measurements of TEMPO⁺ (λ_abs = 290 nm)^[31] showed a new peak with λ_abs = 245 nm after the addition of Li₂CO₃ (Figure 2c). Since carbonate can serve as a reductant and engage in SET with both inorganic complexes and organic molecules,^[32] the UV-Vis data indicate that carbonate reduces TEMPO⁺ to the putative TEMPO^• (λ_abs = 245 nm).^[31] This unprecedented observation is further supported by EPR studies.^[33] Taken together, these results suggested that Li₂CO₃ plays a dual role as a base and a sacrificial reductant to prevent catalyst deactivation.

Figure 2.

Mechanism Studies: ^a The reaction was performed using 5.0 equivalents of 2a/2a-d_6, respectively. DFT and Marcus theory calculations were performed at the M06–2X/6–311++G(d,p)/SMD(MeCN)//M06–2X/6–31+G(d) level of theory using benzene as the substrate. All energies are in kcal/mol and are with respect to Ia and 1a. See SI for details. DET = dissociative electron transfer; SET = single electron transfer; and HAT = hydrogen atom transfer.

We performed computational studies to evaluate the energy profiles of the proposed SET reaction mechanism and another plausible catalytic cycle involving HAT by TEMPO^• (Figure 2d). DFT and Marcus theory calculations suggested that the formation of the difluoromethoxyl radical (^•OCF₂H) and TEMPO⁺ via the dissociative electron transfer (DET)^[34] is feasible with an activation free energy of +12.8 kcal/mol and is exergonic by –11.2 kcal/mol. The addition of the ^•OCF₂H to an arene to give cyclohexadienyl radical IIa is slightly exergonic with a ΔG° of –2.6 kcal/mol. Single-electron oxidation of IIa by TEMPO⁺ to form cyclohexadienyl cation IIb and regenerate TEMPO^• catalyst is kinetically favored by –8.5 kcal/mol as compared to the sterically challenging HAT (ΔG^‡ = 18.7 kcal/mol with respect to IIa).^[35],[36] Deprotonation of IIb to form the desired product 3a is highly favorable with a ΔG° of –82.2 kcal/mol. Collectively, the experimental and computational studies support the proposed catalytic cycle shown in Scheme 1.

In summary, we have developed the first application of redox-neutral TEMPO^• catalysis to achieve intermolecular di- and trifluoromethoxylation of (hetero)arenes. Our strategy uses the readily available and inexpensive TEMPO^• catalyst, exhibits high functional group tolerance, and offers flexible late-stage functionalization of drug-like molecules. Detailed experimental and computational studies suggest that (i) the reaction proceeds through an oxidative TEMPO^•/TEMPO⁺ redox cycle, and (ii) Li₂CO₃ prevents catalyst deactivation. We anticipate that these new findings and mechanistic insights will aid in the development of a new class of reactions in the area of nitroxyl radical chemistry.