Redox-active Reagents for Photocatalytic Generation of the OCF3 Radical and (Hetero)Aryl C-H Trifluoromethoxylation

Abstract

The trifluoromethoxy (OCF₃) radical is of great importance in organic chemistry. Yet, catalytic and selective generation of this radical at room temperature and pressure remains a longstanding challenge. Herein, we report the design and development of a redox- active cationic reagent 1 that enables the formation of the OCF₃ radical in a controllable, selective, and catalytic fashion under visible light photocatalytic conditions. More importantly, the reagent allows catalytic, intermolecular C-H trifluoromethoxylation of a broad array of (hetero)arenes and biorelevant compounds. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1 resulting in exclusive liberation of the OCF₃ radical. Addition of this radical to (hetero)arenes gives trifluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of trifluoromethoxylation.

Graphical Abstract

One Radical at a Time: Redox-active cationic OCF3 reagents enable catalytic and selective formation of the OCF₃ radical under visible-light photocatalytic conditions. Its synthetic utility is highlighted by late-stage C-H trifluoromethoxylation of (hetero)arenes and biorelevant molecules.

The OCF₃ radical is of significant interest to synthetic chemists because this open shell intermediate has reactivity that is complementary with and difficult-to-achieve by the OCF₃ anion.^[1] While the weakly nucleophilic CF₃O anion often requires activated electrophiles such as carbocations,^[2] the reactive OCF₃ radical reacts favourably with unactivated organic compounds (e.g., benzene) than undergoes self-decomposition (Scheme 1a). Thus, easy-to-handle reagents capable of liberation of the versatile OCF₃ radical at room temperature are highly desired because it not only creates a reaction platform for the design and development of novel trifluoromethoxylation reactions of hydrocarbons but also provides direct access to underexplored OCF3 chemical space.^[3]

Scheme 1.

Formation and reactions of the OCF₃ radical.

Seeking to develop OCF₃-radical reagents for trifluoromethoxylation of hydrocarbons, we took advantage of the weak N-OCF₃ bond (BDE = 53.1 kcal/mol) and recently reported a photoactive OCF₃-reagent that could be photolyzed under irradiation of violet light (λ_max = 402 nm) to form the OCF₃ radical and an N-centered benzimidazole radical (Scheme 1b).^[3m] Although the reagent is capable of trifluoromethoxylation of arenes, the reaction is complicated by the formation of the N-arylated side products (3%−10%). Also, the formation of the OCF₃ radical is a stochiometric process because whenever the reagent is photoexcited, the N-OCF₃ bond would homolyze to form two radical species. We questioned whether the OCF₃ radical could be generated catalytically and selectively using a redox-active OCF₃-reagent. Herein, we report the design and development of such a reagent bearing benzotriazole core for a direct, catalytic C-H trifluoromethoxylation of (hetero)arenes (Scheme 1c).

Our redox-active reagents are based on 1-hydroxy-benzotriazole scaffolds because these compounds, widely used in peptide synthesis, are inexpensive. Also, they can be easily prepared through a one-step condensation reaction of ortho-halonitrobenzene with hydrazine, which allows rapid exploration of the structure-reactivity relationship of OCF₃-reagents.^[4] Moreover, we have successfully established a reaction protocol for the synthesis of 1-OCF₃-benzotriazole compounds (e.g., A, Table 1). More importantly, O-acylated 1-hydroxy-benzotriazoles are capable of accepting an electron to form the corresponding radical anion leading to the mesolytic cleavage of the N-O to afford an O-centered radical.^[5] Thus, a series of 1-OCF₃- benzotriazole reagents were synthesized.

Table 1.

Selected Optimization Experiments^[a]

^[a]10 equivalents of 2a was used.

^[b]Yields were determined by ¹⁹F-NMR using PhCF₃ as an internal standard.

^[c]1 equivalent of 2a was used.

^[d]Without light.

^[e]Under air atmosphere.

^[f]With100 equivalent of H₂O.

Photoredox catalysis has recently emerged as a powerful tool in organic synthesis.^[6] We hypothesised that an appropriate combination of photoredox catalysts and 1-OCF₃-benzotriazole reagents would allow the catalytic formation of the OCF₃ radical via a sequential SET process. An initial attempt of subjecting compound A to a mixture of 1,3,5-trichlorobenzene (2a, 10 equiv) and Ru(bpy)₃(PF₆)₂ (1 mol%) in MeCN (0.200 M) under irradiation of 10 W blue LED light (λ_max = 447 nm) failed to produce the desired product 3a (Table 1, entry 1). Presumably, this is due to the highly negative reduction potential of A (E_p = −1.97 V vs SCE, Fig. S12). Even if the corresponding radical anion can be accessed, DFT calculations show that the mesolytic cleavage of the N-OCF₃ bond would favour the formation of the N-centered benzotriazole radical rather than the OCF₃ radical because of the electron withdrawing group (e.g., CF₃) on the O-atom (Fig. S6).^[3m,^7] We reasoned that cationic N-OCF₃ reagents would be better electron acceptor and the resulting reduced neutral radicals would fragment to form the OCF₃ radical selectively (Scheme 2a). Indeed, using methylated cationic reagent B instead of A under otherwise identical conditions gave 3a in 60% yield along with 33% of byproducts B’ (entry 2).^[8] Deactivation of the benzotriazole ring with an addition of a nitro-group (reagent 1) suppressed the formation of B’ and increased the product yield to 70% (entry 3). Using a solvent mixture of MeCN and CH₂Cl₂ (1:1 v/v) further improved the yield to 84% (entry 4) and no N-arylated side product was observed. The reaction also worked with one equivalent of trichlorobenzene albeit in a lower yield and accompanied by 15% of bis-trifluoromethoxylated product (entry 5). Control experiments confirmed the necessity of the visible light and photoredox catalysts (entries 6 and 7). Notably, the reaction proceeded under an air atmosphere or in the presence of water without loss of reactivity (entries 8 and 9).

Scheme 2.

Reaction energies and the proposed catalytic cycle. DFT 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 II and 1. See SI for details.

With the optimized conditions (Table 1, entry 4) in hand, we turned our attention to explore the generality of the transformation. To our delight, a wide range of mono-, di-, and tri-substituted (hetero)arenes reacted well to afford the desired C-H trifluoromethoxylation products. Functional groups such as halides (F, Cl, Br, 2a-2g, 2s-2t, 2v-2ab, 2ae-2ag, and 2ai-2aj), carboxylic acids (2g-2h, 2aj), ketones (2i and 2ae), esters (2j-2k, 2u, 2ac, 2ae-2ah), aldehyde (2aa), substrates with weak benzylic hydrogen atoms (BDE = ~88 kcal/mol, 2m, 2v-2w, 2ad and 2ah),^[9] nitrile (2o, 2z, and 2ad), sulfonyl (2q and 2ai), phosphine oxide (2r), and CF₃ (2f) groups are all tolerated. In contrast to the previously reported photoactive reagent,^[3m] redox-active reagent 1 could be used to functionalize electron rich arenes such as toluene (2m) and tert-butyl benzene (2n), affording the desired products in synthetically useful yields. Notably, heteroarenes such as pyridine, pyrimidine, and thiophene (2s-2ad), found in thousands of medicinally important structures, could also be used in this reaction. Although ten equivalents of arenes were used, we could recover 7.9–9.2 equivalents of aromatic substrates at the end of the reaction, which is critical for valuable arenes. The synthetic utility of this process is further highlighted by its amenability to a late-stage trifluoromethoxylation of biorelevant molecules using arenes as a limiting reactant. For example, trans-androsterone, diacetonefructose, L-menthol (analgesics and decongestants), and Metronidazole^® (antibiotic) derivatives reacted to afford the desired OCF₃-analogs (3ae-3ah) in modest yields based on the recovery of starting materials. Other marketed drugs such as Chlorpropamide^® (anti-diabetic drug, 2ai) and Baclofen^® (muscle relaxant, 2aj) were viable substrates as well.

The regioselectivity of the reaction resembles other radical- mediated aromatic substitution processes and is guided by the electronics of the substituent except in the case of a bulky substituent, for example, substrate 2o, where the OCF₃ radical adds preferably to the position distal from the tert-Bu group. Also, if an aromatic substrate has multiple reaction sites, the OCF₃ radical will add to these sites to form regioisomers. Isolation of these regioisomers allows rapid biological-activity assays of OCF₃-analogs and accelerates the discovery of new drugs.^[10]

Our unique ability to catalytically and selectively generate the OCF₃ radical at ambient conditions allows studying its property and reactivity in organic solvents. Intermolecular competition experiments demonstrated that the electrophilic OCF₃ radical reacts favourably with an electron-rich arene (Fig. S8). Deuterium kinetic isotope effect (KIE) studies showed no KIE (Fig. S9), which rules out the possibility of H-atom abstraction/deprotonation as the rate-determining step. Determination of the quantum yield and quenching constant via Stern-Volmer quenching studies proved to be challenging because the Ru(bpy)3²⁺ sensitiser and reagent 1 both absorb in the visible light region (Fig. S3 and S4). Nevertheless, light on/off experiments showed that the reaction halted when the irradiation stopped (Fig. S10), which indicates that a long radical chain mechanism is unlikely. This corroborates with DFT calculations, where SET between Ru(bpy)3³⁺ and IV is favourable by ΔG = −25.7 kcal/mol (Fig. S7). Since the reaction is insensitive to oxygen (Table 1, entry 8), reagent 1 should quench excited Ru(bpy)₃²⁺ faster than molecular oxygen and have the quenching constant of at least 2.7 × 10⁹ s⁻¹.^[11] Finally, DFT calculations showed favourable SET between excited *Ru(bpy)3²⁺ and 1 to form neutral radical 1a (ΔG = −20.9 kcal/mol) that readily undergoes homolytic cleavage of the N-OCF₃ bond (ΔG = −22.4 kcal/mol), thereby catalytically and exclusively delivering the OCF₃ radical (Scheme 2a).

Based on the collective results, a catalytic cycle proposed in Scheme 2b serves as a working mechanistic hypothesis. Initial excitation of the Ru(bpy)₃²⁺ (I, bpy = 2,2’-bipyridine) produces the long-lived triplet-excited state of *Ru(bpy)₃²⁺ (II, t_1/2 = 1.1 μs).^[12] Catalyst II is sufficiently reducing (E½^red = −0.81 V) to undergo SET with the redox-active reagent 1 (E_p = +0.140 V, vs SCE in CH₃CN, Fig. S10) to generate Ru(bpy)3³⁺ and neutral radical 1a that fragments to exclusively liberate the OCF₃ radical. Its addition to an arene to form cyclohexadienyl radical IV is thermodynamically favourable (ΔG = −9.2 kcal/mol). Oxidation of IV by Ru(bpy)3³⁺ affords cyclohexadienyl cation V, which is deprotonated to give the desired product of trifluoromethoxylation.

In conclusion, we describe the air- and moisture-stable, redox-active reagent 1 that enables catalytic and selective generation of the OCF₃ radical under visible-light photocatalytic conditions at room temperature. A key design feature of the reagent is its cationic nature that favours the formation of a single OCF₃ radical species after the SET reduction. Reagent 1 is applicable to the synthesis of an important class of OCF₃-arenes and late-stage C-H trifluoromethoxylation of biorelevant molecules. Mechanistic studies suggest a catalytic cycle distinct from the previously reported photoactive OCF₃-reagent. Upon completion of this work, Togni et al. reported an elegant radical trifluoromethoxylation reaction using the similar concept.^[13] Their protocol uses cationic pyridinium OCF3 reagents, first developed by Umemoto and Hu,^[14] to generate the OCF₃ radical under photocatalytic conditions. We anticipate that the unique ability to catalytically access the OCF₃ radical using their and our reagents will open a new avenue for the development of trifluoromethoxylation reactions to aid the discovery of novel functional molecules.

Table 2.

Selected Examples of (Hetero)aryl C-H Trifluoromethoxylation^a

^[a]Reactions were performed using 1 equivalent of 1 and 10 equivalents of (hetero)arenes. Yields and regioselectivity were determined by ¹⁹F-NMR using PhCF₃ as an internal standard.

^[b]MeCN was used as the solvent.

^[c]Reactions were performed using 1 equivalent of substrates and 2 equivalents of reagent 1. The isolated yield based on the recovered starting material.

^[d]Yield in parenthesis is of isolated yield.