A unified photoredox-catalysis strategy for C(sp3)–H hydroxylation and amidation using hypervalent iodine† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc02773g Click here for additional data file.

We report a unified photoredox-catalysis strategy for both hydroxylation and amidation of tertiary and benzylic C–H bonds.


Introduction
Methods for efficient and selective alkyl C-H oxidation could streamline the synthesis of ne chemicals, natural products, and drug metabolites. 1,2 Despite rapid advances in the development of metal-catalyzed reactions 3 and reagents, 4 synthetically useful C(sp 3 )-H oxygenation chemistry is still in great demand. 5,6 Recently, radical reactions mediated by hypervalent iodine(III) reagents have emerged as viable means to oxygenate C(sp 3 )-H bonds under mild conditions. 7- 11 Ochiai rst reported the oxidation of activated C(sp 3 )-H bonds of benzyl and allyl ethers to the corresponding esters using t-butylperoxy benziodoxole (Bl-OOtBu, 1) via H-abstraction by benziodoxole radical Blc 2 (Scheme 1A). 9 Maruoka elegantly demonstrated the use of acyclic iodane reagents 3 and 5 in the selective oxidation of unactivated methylene C-H bonds of simple alkanes to the corresponding ketones, effected by more reactive iodanyl radical intermediates 4 and 6. 10 Notably, Maruoka's oxygenation reactions proceed with a selectivity for secondary over tertiary C-H bonds. Herein, we report an efficient and broadly applicable photoredox-catalysis strategy for the selective hydroxylation of tertiary and benzylic C-H bonds using hydroxyl benziodoxoles as oxidant and H 2 O as cosolvent and hydroxylation reagent. This reaction system can be easily modulated to Scheme 1 C(sp 3 )-H oxygenation and amination with hypervalent iodine(III). achieve tertiary and benzylic C-H amidation with high efficiency and selectivity using CH 3 CN as co-solvent and amidation reagent.

Results and discussion
Previously, we discovered a visible light-promoted method for tertiary C-H azidation using Zhdankin reagent Bl-N 3 11 (see entry 1, Table 1), [Ru(bpy) 3 ]Cl 2 photosensitizer, and household compact uorescent lamp (CFL) irradiation. [12][13][14] We proposed a radical chain mechanism for this azidation reaction, beginning with formation of Bl radical 2 via single electron reduction of 11 by a photoexcited Ru(II)* species. Blc 2 then selectively abstracts a H atom from the substrate (e.g. 4-methylpentyl benzoate 7), forming tertiary alkyl radical intermediate, which reacts with 11 to give C-H azidation product and regenerate radical 2, propagating a radical chain reaction. Encouraged by these results, we questioned whether the reaction with the corresponding hydroxyl benziodoxole could offer C-H hydroxylation product under similar conditions. As shown in Table 1, we commenced the investigation of tertiary C-H hydroxylation of 7 with Bl-OH 13 under the irradiation of CFL (23 W) using [Ru(bpy) 3 ]Cl 2 as photocatalyst in hexauoroisopropanol (HFIP) at 30 C. Our previous work has shown that Bl-OH 13 can be used to generate Blc 2 under similar conditions for a Minisci-type C-H alkylation reaction of N-heteroarenes with alkyl boronic acids. 15,16 However, subjecting 7, 13, and [Ru(bpy) 3 ]Cl 2 to CFL irradiation produced only trace amount of the desired hydroxylation product 8, with 7 largely unconsumed (entry 2). However, adding H 2 O to the reaction increased the yield of 8 to 29% (entry 3). Our previous work has indicated that the spin density of Blc is delocalized on both O and I atoms and that Blc is more stable than benzoyloxy radical BzOc. 15 The stability of Blc may explain the observed weak reactivity for H-abstraction and the low conversion of 7. 17, 18 We speculated that installation of electron-withdrawing groups on the aryl motif of Bl would increase its electrophilicity, and enhance its H-abstraction reactivity. As shown in entries 4-7, Bl-OH analogs 14-17 with different electronwithdrawing groups were prepared and evaluated (see ESI † for more details). 19 We were pleased to nd that these Bl-OH analogs provided improved results, and hydroxyl per-uorobenziodoxole (PFBl-OH, 17) gave the best yield. 20,21 A 64% isolated yield of 8 was obtained when 2.5 equiv. of 17 was used (entry 10). Regarding the optimization of this hydroxylation reaction, we note: (1) addition of H 2 O is critical to obtain high yield (see entries 10 vs. 17).
(2) 17 has high polarity and only dissolves well in polar solvents such as HFIP, DMSO, DMF; HFIP gives signicantly better results than other solvent tested; (3) under O 2 atmosphere, the reaction gave signicantly diminished yield (entry 12); (4) in the dark, the reaction gave no product (entry 15); (5) only trace amount (<3% yield) of methylene C-H hydroxylation side product was detected. Interestingly, when the reaction was performed in mixed HFIP/CH 3 CN solvents (4/3) under similar conditions we obtained 56% yield of the C-H aminated product 10 with excellent selectivity (entry 20). With optimized conditions in hand, we investigated the substrate scope of this C-H hydroxylation reaction (Scheme 2). In general, the reaction proceeds with excellent selectivity for tertiary C-H bonds and in good yield. Common functional groups including CN, iodo, esters, amide, imide and pyridine moiety are tolerated. When reaction of 7 was performed in a mixture of HIFP and H 2 18 O (97% of 18 O), 18 O-labelled product 19 was obtained. C-H hydroxylation of sulbactam and thalidomide derivatives (see 27 and 28) bearing b-lactam and imide groups proceeded in good yield. 28 was obtained in 60% yield on a gram scale. Both steric and electronic factors inuence the reactivity of tertiary C-H bonds. For instance, tertiary C-H hydroxylation took place selectively at the more distal 3 carbon of 29. Hydroxylation of the sterically hindered and electron-poor tertiary C-H bond of phthaloyl valine methyl ester gave 32 in moderate yield. In comparison, C-H hydroxylation of leucine methyl ester 34 provided lactone product 33 in 52% yield. Moreover, short peptide substrates (see 35 and 36) can be C-H hydroxylated on the Leu residue with excellent selectivity under standard conditions. While a number of methods for oxidation of benzylic methylene groups to ketones have been developed, 22 practical methods for C-H hydroxylation of these methylene groups to benzyl alcohols are sparse. 23 As shown in Scheme 3, we subjected 4-ethylphenyliodide to our standard C-H hydroxylation conditions with PFBl-OH 17, and obtained the alcohol product 37 in 40% yield along with 22% of ketone 37 0 and other unidentied by-products. We were delighted to nd that use of 2 equiv. of Bl-OH 13 under the same conditions gave 37 in 71% yield along with 8% of ketone. More ketone 37 0 (24%) was obtained when 4 equiv. of Bl-OH was used for extended reaction time (24 h). This Bl-OH mediated benzylic C-H hydroxylation exhibited excellent chemo-selectivity and broad substrate scope. The reaction tolerates functional groups such as iodo, ketone, amide, even pinacolyl boronate ester (see 42). Electron-decient arenes are less reactive and require the use of 4 equiv. of Bl-OH 13 (see 41). Electron-rich substrates give good yield with 1.5 equiv. of Bl-OH (see 38). Reaction of ibuprofen methyl ester gave 43 in 64% yield without the formation of tertiary C-H hydroxylated product. The same reaction in H 2

18
O gave 18 Olabelled product 44. Reaction of natural product celestolide gave product 45 in excellent yield.
As shown in Scheme 4, by simply switching to the HFIP/ CH 3 CN solvents, this hydroxyl benziodoxole-mediated reaction system provides an excellent method for C(sp 3 )-H amidation, which remains a challenging transformation for C-H functionalization chemistry. 24,25 Tertiary C-H amidation with PFBl-OH 17 and benzylic C-H amidation with Bl-OH 13 proceeded with yields and regio-selectivity similar to the corresponding C-H hydroxylations carried out in HFIP/H 2 O solvents. Unactivated methylene C-H bonds were generally unreactive with either 13 or 17. However, cycloalkanes such as cyclohexane were efficiently amidated with 17 (see 51), probably due to their slightly more activated C-H bonds and more favorable kinetics. 25b Product 54 carrying a benzamide group was obtained in good yield using HFIP/PhCN solvent under similar conditions. Generally, the competing C-H hydroxylation reactions were well suppressed (<2% yield) in HFIP/nitrile solvents.
As shown in Scheme 5A, two C-O bond forming mechanisms were initially considered for this C-H hydroxylation reaction: nucleophilic trapping of a carbocation intermediate with H 2 O (pathway a) or a radical chain reaction with the hydroxyl benziodoxole reagents (pathway b). 23c In contrast to the large quantum yield F observed in our previously reported visible light-promoted C-H azidation reaction with Bl-N 3 11, 12 a small F (0.85, measured by Yoon's method 26 ) of the C-H hydroxylation reaction of 7 with PFBl-OH 17 suggested a non-radical chain mechanism (see ESI † for details). The dependence of the reactivity on the H 2 O co-solvent and the formation of amidation product in the presence of CH 3 CN product strongly support ionic pathway a. Stern-Volmer experiments conrmed that the excited state of photocatalyst [Ru(bpy) 3 ]Cl 2 can be quenched by the addition of PFBl-OH 17, while no obvious luminescence change of the photocatalyst was observed in the presence of substrate 7 (see ESI † for details). 27 The mechanism of tertiary C-H hydroxylation with PFBl-OH 17 likely begins with single electron transfer (SET) from photoexcited Ru(II)* to PFBl-OH 17, generating radical PFBlc 55.   25b We speculate that Bl-OH mediated benzylic C-H hydroxylation and amidation proceeds through a similar mechanism, involving cleavage of benzylic C-H bond with less electrophilic Blc 2. This mechanism is supported by density functional theory (DFT) calculations using t-butane as a model substrate (Scheme 5B). The initial SET reduction of PFBl-OH 17 to PFBlc 55 is signicantly more exergonic than the SET with Bl-OH 13 to Blc 2 (DG ¼ À4.9 kcal mol À1 with PFBl-OH 15 vs. À0.9 kcal mol À1 with Bl-OH 13). 28,29 With its spin density delocalized over the O and I atoms, PFBlc 55 undergoes facile H-abstraction of t-butane through an O-centered transition state (TS1) with a DG ‡ of 16.6 kcal mol À1 to give tBuc. 30 This H-abstraction process is promoted by the electron-decient peruoroaryl group. The corresponding H-abstraction with Blc 2 requires a noticeably higher barrier of 18.2 kcal mol À1 (see ESI †). The subsequent oxidation of tBuc by Ru(III) to tbutyl cation is highly exothermic. Finally, the tbutyl cation is trapped with H 2 O, providing tBuOH. Taken together, the DFT calculations indicated the per-uorinated analogue PFBl-OH promotes both the initial SET reduction and the H-abstraction steps in the catalytic cycle of the tertiary C-H hydroxylation.

Conclusions
In summary, we have developed a unied photoredox-catalysis strategy for both C(sp 3 )-H hydroxylation and amidation using hydroxyl benziodoxole oxidant. This strategy allows the selective functionalization of tertiary and benzylic methylene C-H bonds under mild conditions. These reactions exhibit excellent substrate scope, and offer an efficient and convenient method for late-stage derivatization of complex substrates. Distinct from the radical chain mechanism invoked for our previous tertiary C-H azidation reaction with azido benziodoxole, we propose a new product-forming pathway: photoredox catalyzed formation of a carbocation intermediate, followed by nucleophilic trapping with H 2 O or nitrile cosolvent. Further expansion of the nucleophile scope and the functionalization of unactivated methylene C-H bonds using this reaction system are currently under investigation.

Conflicts of interest
There are no conicts to declare.