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1. Radical cascade synthesis of azoles via tandem hydrogen atom transfer

   https://doi.org/10.1039/c9sc06239d  

   Chen, Andrew D.; Herbort, James H.; Wappes, Ethan A.; Nakafuku, Kohki M.; Mustafa, Darsheed N.; Nagib, David A. (March 2020, Chemical Science)

   null (Ed.)

   A radical cascade strategy for the modular synthesis of five-membered heteroarenes ( e.g. oxazoles, imidazoles) from feedstock reagents ( e.g. alcohols, amines, nitriles) has been developed. This double C–H oxidation is enabled by in situ generated imidate and acyloxy radicals, which afford regio- and chemo-selective β C–H bis-functionalization. The broad synthetic utility of this tandem hydrogen atom transfer (HAT) approach to access azoles is included, along with experiments and computations that provide insight into the selectivity and mechanism of both HAT events. 

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2. Strain Release in Hydrogen Atom Transfer from 1,4-Disubstituted Cyclohexanes to the Cumyloxy Radical

   https://doi.org/10.1055/a-2522-6204  

   Galeotti, Marco; Palone, Andrea; Salamone, Michela; Liu, Fengjiao; Yu, Yanmin; Houk, K N; Bietti, Massimo (June 2025, Synlett)

   Abstract A kinetic, product, and computational study on the reactions of the cumyloxyl radical (CumO•) with 1,4-dimethyl- and 1,4-diphenylcyclohexanes is reported. The rate constants for hydrogen atom transfer (HAT) from the C–H bonds of these substrates to CumO•, together with the corresponding oxygenation product distributions reveal the role of strain release on reaction site selectivity. Transition structures and activation barriers obtained by DFT calculations are in excellent agreement with the experimental results. Tertiary/secondary ratios of oxygenation products of 0.6, 1.0, and 3.3 were observed, for trans-1,4-dimethyl-, cis-1,4-dimethyl-, and trans-1,4-diphenylcyclohexane, respectively. With cis-1,4-diphenylcyclohexane, exclusive formation of the diastereomeric tertiary alcohol products was observed. Within the two diastereomeric couples, the tertiary equatorial C–H bond in the cis- isomer is ca. 6 and 27 times more reactive, respectively, than the tertiary axial ones, a behavior that reflects the release of 1,3-diaxial strain in the HAT transition state. The tertiary axial C–H bonds of the four substrates show remarkably similar reactivities in spite of the much greater stabilization of the benzyl radicals resulting from HAT from the 1,4-diphenylcyclohexanes. The lack of benzylic acceleration is discussed in the framework of Bernasconi’s ‘principle of nonperfect synchronization’. 

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3. Remote C–H Functionalization via Selective Hydrogen Atom Transfer

   https://doi.org/10.1055/s-0036-1591930  

   Stateman, Leah; Nakafuku, Kohki; Nagib, David (April 2018, Synthesis)

   The selective functionalization of remote C–H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis. This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways. As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C–H functionalization. This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena. 1 Introduction 2 Nitrogen-Centered Radicals 2.1 sp3 N-Radical Initiation 2.2 sp2 N-Radical Initiation 3 Oxygen-Centered Radicals 3.1 Carbonyl Diradical Initiation 3.2 Alkoxy Radical Initiation 3.3 Non-alkoxy Radical Initiation 4 Carbon-Centered Radicals 4.1 sp2 C-Radical Initiation 4.2 sp3 C-Radical Initiation 5 Conclusion 

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4. A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor

   https://doi.org/10.1038/s41467-021-27165-z  

   Leibler, Isabelle Nathalie-Marie; Tekle-Smith, Makeda A.; Doyle, Abigail G. (November 2021, Nature Communications)

   Abstract Photoredox catalysis has provided many approaches to C(sp³)–H functionalization that enable selective oxidation and C(sp³)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp³)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp³)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp³)–H functionalization. 

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5. β C–H di-halogenation via iterative hydrogen atom transfer

   https://doi.org/10.1039/C8SC01214H  

   Wappes, Ethan A.; Vanitcha, Avassaya; Nagib, David A. (January 2018, Chemical Science)

   A radical relay strategy for mono- and di-halogenation (iodination, bromination, and chlorination) of sp³C–H bonds has been developed. This first example of double, geminal C–H functionalization is enabledviaiterative, hydrogen atom transfer (HAT) byin situgenerated imidate radicals. 

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