Selective C–O bond formation via a photocatalytic radical coupling strategy: access to perfluoroalkoxylated (ORF) arenes and heteroarenes† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc01684k Click here for additional data file.

Synthesis of perfluoroalkoxylated (hetero)arenes (Ar–ORF) from readily available perfluoroalkyl iodides (RF–I) through photocatalytic selective O–RF bond formation.


Introduction
Molecules containing a peruoroalkoxy group (OR F ) have emerged as an important class of compounds in the elds of pharmaceutical, agrochemical, and materials science because incorporation of an OR F group into organic compounds oen improves thermal, chemical and metabolic stability, lipophilicity, and bioavailability of parent molecules. [1][2][3][4][5][6][7][8][9][10] While much progress has been made for late stage uorination, 11,12 per-uoroalkylation, [13][14][15] and peruoroalkylthiolation [16][17][18][19] of (hetero) arenes, the facile synthesis of peruoroalkoxylated (hetero) aromatic compounds remains an unmet challenge in synthetic organic chemistry. 9,[20][21][22][23][24][25] Unlike their analogous alkoxy groups, formation of an O-R F bond (e.g. R F ¼ CF 3 ) via direct S N 2 type displacement is unfavorable due to (i) strong electron repulsion between uorine atoms and incoming nucleophiles and (ii) the formation of an energetically adverse CF 3 carbocation transition state (TS) structure (Fig. 1a). 2,26 Umemoto et al. addressed this issue with an elegant electrophilic O-R F bond formation strategy via radical intermediates, 20 yet the non-selective formation of Oand C-peruoroalkylated products limited its synthetic utility. Although new strategies for the synthesis of peruoroalkoxylated (hetero)arenes have emerged over the past few years, 23,27-32 a general and mild catalytic process has yet to be developed. As a result, the full potential of peruoroalkoxylated (hetero) aromatic compounds has not been fully exploited across a broad spectrum of technological applications.
To address this challenge, we recently developed tri-uoromethoxylation reactions of aromatic compounds using N-(hetero)aryl-N-hydroxylamides and Togni reagents under mild reaction conditions. 33,34 Our operationally simple and scalable protocols provide access to a diverse array of tri-uoromethoxylated (hetero)aromatics with complex molecular architectures. Nevertheless, the high cost and multi-step synthesis of Togni reagents (e.g. Togni reagent I costs $55 980 mol À1 ) 35 might hinder their synthetic application. Furthermore, preparation of other O-peruoroalkylated analogues requires the use of unique hypervalent iodine(III) peruorinating reagents, which are commercially unavailable, syntheticallyinaccessible, and thermally unstable. In order to develop a general method to access peruoroalkoxylated (hetero)arenes, we turned our attention to R F -I reagents (R F ¼ peruoroalkyl) that are commercially available and cost efficient (e.g. CF 3 I costs $83 mol À1 ). 35 Based on our prior mechanistic studies, 36 selective O-R F bond formation is feasible if N-hydroxyl and R F radicals are generated simultaneously. 37 Although direct single electron transfer (SET) from N-(hetero)aryl-N-hydroxylamides to R F -I is kinetically and thermodynamically unfavorable, we hypothesize that such a SET process could be facilitated by using an appropriate photoredox catalyst. 15,38,39 Herein, we describe our efforts to develop the rst photocatalytic radical coupling reaction of N-(hetero)aryl-N-hydroxylamides with R F -I to form N-OR F compounds, which then undergo OR F -migration to afford a wide variety of peruoroalkoxylated (hetero)arenes (Fig. 1b).

Results and discussion
To examine the feasibility of our hypothesis, we started our investigation using N-(p-tert-butylphenyl)-N-hydroxylamide (1a) and peruoroisopropyl iodide (2a) as model substrates. Pleasingly, aer exposure of 1a (1.00 equiv.) and 2a (8.00 equiv.) to visible light irradiation [3 W blue light-emitting diodes (LEDs)] in the presence of a ruthenium photoredox catalyst [Ru(bpy) 3 (PF 6 ) 2 , (0.500 mol%)] and potassium carbonate (3.00 equiv.) in acetonitrile (0.100 M) at 23 C for 12 hours, we obtained the desired product 3a in 38% yield ( Table 1, entry 1). Exploration of photoredox catalysts, solvents, bases, concentrations, reactant stoichiometry and catalyst loading did not improve the product yield (entries 2-5). A breakthrough in optimization came when we lowered the reaction temperature to 0 C, at which an 80% yield of the desired product 3a was obtained (entry 6). It is noteworthy that we did not observe addition of R F radicals directly to arenes even though such a reaction has been developed under photoredox-catalyzed reaction conditions. 15,40 Apparently, this is due to the persistent radical effect that coupling of O-and R F -radicals is more favorable than the addition of R F radicals to arenes. 41,42 Finally, control experiments showed that a photoredox catalyst, a base, light, and an oxygen-free atmosphere are critical for the success of the per-uoroalkylation reaction (entries 7-10).
With the optimized reaction conditions in hand, we explored the scope of the peruoroisopropylation reaction with respect to N-(hetero)aryl-N-hydroxylamides (1a-1t) ( Table 2). 43 The optimized reaction conditions were compatible with both aromatic and heteroaromatic hydroxylamides bearing a wide variety of functional groups and molecular scaffolds. For example, substrates with benzylic hydrogens, which are oen prone to hydrogen atom abstraction in the presence of radical species, are tolerated (3b-3e and 3q-3s). Presumably, the rate of O-and R F -radical coupling is faster than that of benzylic hydrogen atom abstraction. These results further demonstrate the chemoselectivity of our protocol. In addition, halogen functionalities (3f-3i, 3n, 3o and 3q) remained intact aer the reaction, providing easy handles for further synthetic elaborations. Substrates containing polyuoromethyl ethers were also viable and afforded good yields of the desired products (3j and 3k). Moreover, products derived from the heterocyclic N-hydroxylamides such as benzofuran (3l) and benzothiophene (3m) were formed smoothly with high levels of regioselectivity. Other functional groups such as esters (3e and 3m), ketones (3l and 3s), ethers (3q-3t), carbamates (3e), 1,2,4-oxadiazoles (3n), oxindoles (3o), pyrazoles (3p), pyridines (3p-3t) and ketals (3t) were susceptible to OR F addition as well. Importantly, more complex N-pyridinyl-N-hydroxylamides derived from estrone and diacetone-D-glucose could be effectively converted to their peruoroisopropylated analogs (3s and 3t), demonstrating that this method can be used in the preparation of pharmaceutically relevant compounds. Notably, none of the per-uoroisopropylated arenes and pyridines reported herein have been prepared prior to this study.
Triuoromethoxy aryl ethers (Ar-OCF 3 ) are constituents of several pharmaceutically active compounds, agrochemicals, and functional materials. 3,5,6,8,9 As a result, signicant effort has recently been directed towards uncovering general and practical protocols for their preparation, 6,24,25 yet methods that use commercially available CF 3 I for their preparation have not been developed. We were pleased to see that our photocatalytic protocol can also be used for the synthesis of tri-uoromethoxylated arenes (4a-4d) from CF 3 I (Table 3). In general, O-triuoromethylation required a longer reaction time (48 h vs. 12-24 h for heptauoroalkoxylation), possibly due to the lower reduction potential of CF 3 I (E red 1/2 ¼ À1.52 V vs. SCE) 44 in comparison with (CF 3 ) 2 CFI (E red 1/2 ¼ À0.66 V vs. SCE), 44 which required an over-potential of 0.19 V for the reduction of CF 3 I to generate the CF 3 radical using Ru(bpy) 3 + (E red 1/2 ¼ À1.33 V vs. SCE). 45 In addition, other peruoroalkyl iodides such as 1,1,1,2,2,3,4,4,4-nonauoro-3-iodobutane and n- peruorohexyliodide coupled smoothly to afford the desired products (4e and 4f) in synthetically useful yields. Importantly, our reaction is applicable to polyuoroalkyl iodides such as 1chloro-2-iodo-tetrauoroethane and 1-bromo-2-iodotetrauoroethane, albeit that 4h was obtained in a lower yield. This may be due to the instability of the 1-bromotetra-uoroethoxide species generated during the OR F -migration process. It is worth noting that the anilide moiety of the products could serve as a versatile handle for further synthetic functionalizations. 34 In order to get an insight into the mechanism of the photocatalytic reaction, we performed a series of Stern-Volmer quenching experiments (Fig. 2a). While deprotonated N-phenyl-N-hydroxylamide (Ia, E red 1/2 ¼ 0.62 V vs. SCE) 46 efficiently quenched *Ru(bpy) 3 2+ in MeCN with a quenching constant of k q ¼ 7.84 Â 10 9 M À1 s À1 , N-phenyl-N-hydroxylamide (1u) and peruoroisopropyl iodide (2a) quenched the photoexcited photocatalyst (*Ru(bpy) 3 2+ ) only to a minor extent. We also observed that the OR F migration is slower with more electron decient aromatics, which is consistent with our previous observations and suggests an ionic OR F -migration pathway. 36 Based on these results, a detailed description of our proposed photocatalytic cycle for selective O-R F bond formation and the consequent OR F -migration is outlined in Fig. 2b. Irradiation of Ru(bpy) 3 2+ with visible light produces a long-lived (1.10 ms) photoexcited state, *Ru(bpy) 3

2+
. Subsequent radical-radical coupling between Ib and cR F affords O-per-uoroalkylated N-phenyl-N-hydroxylamide Ic, which undergoes heterolytic N-OR F bond cleavage 47,48 followed by recombination of the resulting short-lived ion pair (Id) and then tautomerization to yield the nal peruoroalkoxylated arene product. 36 Table 2 Selected examples of the perfluoroisopropylation of arenes and heteroarenes a a Reaction conditions: 1 (1.00 equiv.), 2a (8.00 equiv.), Ru(bpy) 3 (PF 6 ) (0.500 mol%), K 2 CO 3 (3.00 equiv.) in MeCN (0.100 M) at 0 C. Cited yields are for isolated material. b À40 C. c Following peruoroalkylation, the reaction was heated to 40 C. d Following O-peruoroalkylation, the reaction was ltered, concentrated and the residue was dissolved in MeCN and heated to 80 C. e Following O-peruoroalkylation, the reaction was ltered, concentrated and the residue was dissolved in MeNO 2 and heated to 120 C. See ESI for further experimental details. † Table 3 Selected examples of the polyfluoroalkoxylation of arenes a a Reaction conditions: 1 (1.00 equiv.), 2 (8.00 equiv.), Ru(bpy) 3 (PF 6 ) (0.500 mol%), K 2 CO 3 (3.00 equiv.) in MeCN (0.100 M) at 0 C. Cited yields are for isolated material. b À40 C. c Following O-peruoroalkylation, the reaction was heated to 40 C. d Following O-peruoroalkylation, the reaction was ltered, concentrated and the residue was dissolved in MeCN and heated to 40 C. e Following O-peruoroalkylation, the reaction was ltered, concentrated and the residue was dissolved in MeCN and heated to 80 C. See the ESI for further experimental details. †

Conclusions
In conclusion, we have developed the rst photocatalytic protocol for the synthesis of structurally diverse per-uoroalkoxylated (hetero)arenes. The key to the success of our approach is the ability to concomitantly generate persistent and transient radicals under photoredox-catalyzed reaction conditions, which provide direct access to the challenging O-R F bond formation. Our approach is one of the mildest and most general peruoroalkoxylations of (hetero)arenes reported to date. 9,20-25 It features a broad substrate scope and high functional group compatibility. In addition, the use of commercially available R F I reagents and the excellent chemoselectivity of this reaction represents a considerable advance in the construction of the O-R F bond and should have a signicant impact on the approach towards the synthesis of peruoroalkoxylated aromatic building blocks. The success of this method not only provides access to unexplored chemical spaces to aid the discovery and development of novel drugs, agrochemicals, and functional materials, but also establishes a solid framework for further development of the photocatalytic radical coupling strategy using N-(hetero) aryl-N-hydroxylamides.