Metal-free alcohol-directed regioselective heteroarylation of remote unactivated C(sp3)–H bonds

Construction of C–C bonds via alkoxy radical-mediated remote C(sp3)–H functionalization is largely unexplored, as it is a formidable challenge to directly generate alkoxy radicals from alcohols due to the high bond dissociation energy (BDE) of O–H bonds. Disclosed herein is a practical and elusive metal-free alcohol-directed heteroarylation of remote unactivated C(sp3)–H bonds. Phenyliodine bis(trifluoroacetate) (PIFA) is used as the only reagent to enable the coupling of alcohols and heteroaryls. Alkoxy radicals are readily generated from free alcohols under the irradiation of visible light, which trigger the regioselective hydrogen-atom transfer (HAT). A wide range of functional groups are compatible with the mild reaction conditions. Two unactivated C–H bonds are cleaved and one new C–C bond is constructed during the reaction. This protocol provides an efficient strategy for the late-stage functionalization of alcohols and heteroaryls.

Wu et al. disclose in elegant work alcohol-directed regioselective heteroarylation. Although the individual steps of the cascade are established, the overall sequence represents an interesting and highly useful process. Radical C-H functionalization is a highly active and important research area, although first reports in that area (such as the HLF-reaction) were disclosed a long time ago. In general, reactive amidyl radicals (HLF-reaction) or alkoxyl radicals (Barton nitrite ester reaction) are generated in situ, which then undergo intramolecular 1,5 HAT to give C-centered radicals which can finally be trapped by various reagents. The current method uses PIFA for alkoxyl radical generation from the corresponding alcohols (Suarez variant). The C-radical generated after 1,5 HAT is then trapped intermolecularly by protonated heteroarenes (Minisci reaction). Elegantly, the acid (TfOH) is generated in situ from PIFA. Typical regioselectivities for Minisci-type heteroarylations are observed. Yields are moderate to very good and the scope is well documented. The cascade works for primary, secondary and tertiary alcohols. There are few examples of regioselective radical C-H functionalization comprising C-C bond formation. Remote C-H heteroarylation is not well explored (one example is the authors previous work, as cited in the introduction). This contrasts the many examples on remote C-X bond forming processes. Therefore, I rate the quality of the submitted paper, that is written well, as very high and support publication in Nature Communications subject to modifications: 1) A problem of the method lies in the reagent stoichiometry. By looking at the title, the alcohol should be the limiting reaction component. However, authors use a 5-fold excess of the alcohol. Considering heteroarylation of a sophisticated alcohol this is not acceptable. For complex heteroarenes (see product 3x) this is ok. Therefore, it would be great if authors can provide a protocol B (method B) considering the alcohol as limiting reaction component.

2) Mechanism: I(III)-species 4 is considered as the intermediate, which upon I-O bond homolysis
affords the alkoxyl radical. At the same time an iodanyl radical is cogenerated. The fate of that iodanyl radical is not discussed. Note that the iodanyl radical is also an SET-oxidant or it can also abstract H-atoms. The latter reactivity is not likely herein because authors get a highly regioselective radical formation. The iodanyl radical can also oxidize radical cation IV in my eyes.
3) Is regioselectivity for the formation of 3z perfect? The 1,6-HAT would deliver a stabilized secondary benzylic radical. Please comment on that point.

Response Letter
Dear Dr. Giovanni Bottari, Thanks for your positive reply. We herein respond to the comments from both reviewers point-to-point. The manuscript is slightly modified according to the reviewer's suggestions, and the changes are highlighted. We hope you will be satisfied with this version.
Response to Reviewer 1 1. "One of the attracting points of this reaction is the high selectivity. I am curious that for substrate 3z, did the authors detect any oxidation products at the benzylic C-H bonds?"

Response:
The product 3z was generated in high yield via 1,5-HAT (six-membered cyclic transition state). The benzylic oxidation byproduct formed via 1,6-HAT was not detected by NMR analysis. It might be attributed to that 1,5-HAT is more kinetically favorable in this reaction.
2. "The use of alcohols is 5.0 equiv, had the authors tried to use 1 equiv alcohols as substrates? What is the result?"