Photo-induced selective α/γ-functionalization of aliphatic amines via intramolecular hydrogen atom transfer

Abstract

A general method for site-selective α/γ-C(sp³)–H functionalization of amines has been developed. Regioselective activation of inert C–H bonds is achieved by 1,5/1,7-hydrogen atom abstraction by an oxidatively generated aryl radical. C-radicals thus formed at the α/γ-position of the amine functionality undergo radical conjugate addition to various Michael acceptors and provide the corresponding α/γ-functionalized amines. Good functional group tolerance, the success of gram-scale experiments and the late-stage modification of drug molecules greatly highlight the potential applicability of our method.

---

Introduction

Amines are crucial functional groups widely found in pharmaceuticals, materials, and other functional molecules.¹ The direct functionalization of nitrogen-containing compounds through C–H bond activation enables access to target products without the need for pre-installed leaving groups, garnering significant attention.² Significant progress has been made in the α-functionalization of amines, primarily through intramolecular or intermolecular hydrogen atom transfer (HAT) strategies followed by oxidation and deprotonation.³ In contrast, much less research has focused on β- and γ-functionalization of amines. Transition-metal-catalyzed γ-C–H activation, directed by appropriate directing groups, has helped to bridge this gap (Scheme 1a).⁴ Despite notable advancements, these reactions typically require precious metals and harsh reaction conditions. Moreover, the selectivity of C–H activation is largely governed by the thermodynamic stability of the resulting carbon–metal species, favoring the activation of primary C–H bonds over secondary ones, while the activation of tertiary C–H bonds remains minimal.⁵

Scheme 1 Current status of the selective γ-functionalization of aliphatic amines.

In contrast, radical-mediated intramolecular hydrogen atom transfer (HAT) offers an efficient approach for cleaving inert C(sp³)–H bonds especially tertiary C–H bonds—under mild conditions and without precious metals. Within this framework, modifying the HAT site using aryl radicals via heteroatom incorporation has emerged as an attractive strategy. Despite its potential, this approach has received limited attention from the synthetic community and remains underexplored, mainly due to the harsh conditions traditionally required. Conventional methods typically employ unstable diazonium compounds,⁶ highly toxic organotin reagents,⁷ and high-energy light input (wavelength < 320 nm),⁸ which present challenges: they are difficult to implement, struggle to overcome the high reduction potential of halides, and hinder efficient electron transfer. Consequently, developing a mild method that utilizes aryl radicals—generated from inexpensive, easily installable precursors—to functionalize inert C(sp³)–H bonds is highly desirable.

In recent years, substantial progress has been made in aryl radical-mediated intramolecular hydrogen atom transfer (HAT).⁹ However, current methods predominantly focus on α-functionalization of amines, while γ-functionalization remains underexplored. Baran and co-workers reported a stable, easily prepared aryl diazonium salt precursor that enables the remote desaturation of amines.^9b Subsequently, Ragains's group developed a method for remote hydroxylation of amines utilizing aryl diazonium salt precursors.^9c Although diazonium salts exhibit low reduction potential that facilitates reactivity, their in situ generation typically requires stoichiometric strong acids, thereby limiting substrate scope. Gevorgyan's group^9e reported a Pd-catalyzed, highly selective desaturation of aliphatic amines at the α-, β-, and γ-positions without exogenous photosensitizers or oxidants. Meanwhile, independent work from El-Sepelgy's group^9h and Xu' group^9j achieved similar reactivity with low-cost cobalt catalysts, each employing a visible-light-driven, cobaloxime-catalyzed intramolecular HAT strategy that enables chemoselective and regioselective desaturation of amines and amides via radical translocation and Co-assisted β-hydride elimination. Their approach employs efficient metal catalysts for halogen atom abstraction and leverages inexpensive, readily available acyl chlorides to achieve intramolecular halogen atom transfer (Scheme 1b). Nevertheless, due to the inherent instability of alkyl-metal species and competing β-H elimination—particularly with palladium or cobalt catalysts capable of generating aryl radicals—metal-catalyzed functionalization of unactivated C(sp³)–H bonds via aryl radicals has primarily yielded desaturation products.¹⁰ Consequently, constructing all-carbon quaternary centers remains a significant challenge in transition-metal catalysis.

Given these limitations, the development of a practical and universal method for site-selective functionalization of amines is highly desirable. Herein, we report a visible-light-induced method for remote sp³ C–H functionalization of amines via halogen atom transfer (XAT) using aryl radicals. This approach avoids the use of toxic reagents and enables both α- and γ-functionalization of amines. Furthermore, it facilitates cross-electrophile coupling, Heck-type olefination, C–H arylation, and radical defluorinative cross-coupling protocols (Scheme 1c).

Results and discussion

Our study began with the investigation of the reaction of 1a and 1b (Table 1). After a comprehensive investigation of the reaction parameters, we were pleased to find that the combination of the two reactants with [Ir(dF(CF₃)ppy)₂(dtbbpy)]PF₆ (1 mol%), 1,1,3,3-tetramethylguanidine (TMG, 70 μL), and iBu₃N (140 μL) in MeCN at room temperature for 24 h leads to the formation of product 1c in 83% yield. Further optimization was carried out by screening a variety of photocatalysts, such as 4CzIPN and Ir(ppy)₃, but they all provided unsatisfactory results (entries 2 and 3). Control experiments indicated that no desired reaction occurred in the absence of base, photocatalyst, light, or iBu₃N (entries 4–12).

Table 1 Optimization studies^a

Entry	Deviation	Yields^b
a Reaction conditions: 1a (0.2 mmol), 1b (1.5 equiv., 0.3 mmol), [Ir(dFCF3ppy)2(dtbpy)PF6] (1 mol%), TMG (70 μL), MeCN (1 mL) and iBu3N (140 μL) under a nitrogen atmosphere irradiated with a 10 W LED for 6 h at room temperature. b Yields of isolated products are reported.
1	None	83%
2	PC-1 instead of PC-2	42%
3	PC-3 instead of PC-2	Trace
4	(TMS)3SiOH instead of (i-Bu)3N	Trace
5	(TMS)3SiH instead of (i-Bu)3N	Trace
6	Bn3N instead of (i-Bu)3N	21%
7	Without TMG	Trace
8	No light	0%
9	Carried out at 100 °C in the dark	0%
10	Without (i-Bu)3N	Trace
11	Without catalyst under 450 nm	0%
12	Without catalyst under 390 nm	Trace

---

We explored the general applicability of the new methodology for γ-alkylation of amines. As shown in Scheme 2, 2-iodobenzoyl chloride derived benzamides are effective substrates for remote functionalization. Substrates bearing diverse chain lengths showed considerable compatibility, and γ-alkylated products were obtained (2c–7c, 48–87%). The substrates containing different types of γ-tertiary C(sp³)–H bonds were well tolerated and furnished the desired products in moderate yields (8c–10c, 35–48%). Compared to 1,7-HAT, the regioselectivity of 1,6-HAT (14c) is relatively low, while 1,8-HAT (15c) does not occur at all. Finally, alkylation of an enantiopure chiral pool derivative was successfully explored for the leucine derivative (13c, 42% yield). Gratifyingly, peptide molecules with complex structures and multiple HAT prone sites can also be successfully modified in good yields in this system (16c–20c, 47–63%). This is something that is difficult for other methods to achieve. The system demonstrated excellent compatibility with Michael acceptors bearing diverse functional groups (including esters, allyl, and pyridyl moieties), affording the corresponding products in good to excellent yields (21c–31c). Encouraged by the results of the Giese reaction, we proceeded to investigate other transformations. This new coupling protocol allows the union of vinyl sulfones with HAT-generated γ-amino radicals to provide allylic amines in good yields (32c, 66%). α-Trifluoromethyl alkenes are also compatible with this reaction system to generate gem-difluoroalkenes (33c, 65%). It is worth mentioning that high E-stereoselectivity (34c, E : Z = 93 : 7) could be achieved when gem-difluorostyrene was tested. This is due to the ability of iridium to isomerize olefins into less stable isomers, which is difficult to achieve using other catalytic methods.¹

Scheme 2 Substrate scope for γ-alkylation of amines. Reaction conditions: a (0.2 mmol), b (1.5 equiv., 0.3 mmol), [Ir(dFCF₃ppy)₂(dtbpy)PF₆] (1 mol%), TMG (70 μL), MeCN (1 mL) and (iBu)₃N (140 μL) under a nitrogen atmosphere irradiated with a 10 W LED for 6 h at room temperature. ^aYields of isolated products are reported. ^b(E)-(2-(Methylsulfonyl)vinyl)benzene was used. ^c4-(2,2-Difluorovinyl)-1,1′-biphenyl was used. ^d4-(3,3,3-Trifluoroprop-1-en-2-yl)-1,1′-biphenyl was used. ^e2-(Methylsulfonyl)benzo[d]thiazole was used.

We next explored the general applicability of the new methodology for α-alkylation of amines. As shown in Scheme 3, 2-iodobenzenesulfonyl chloride derived sulfonamides are effective substrates for remote functionalization. Substrates bearing diverse chain lengths with considerable α-tertiary C(sp³)–H bonds were well tolerated (36c–38c, 75–95% yields). Cyclic amines of various ring sizes are readily tolerated, with pyrrolidine, piperidine, and azepane undergoing selective C–H alkylation (39c–41c, 75–94% yield). A broad range of cyclic amines, including those bearing alkoxyl (42c, 43c), ester (44c), sulfone (45c), and amino (47c, 48c) groups, were successfully employed in this protocol, yielding the corresponding alkylation products in moderate to good yields.

Scheme 3 Substrate scope for α-alkylation of amines. Reaction conditions: a (0.2 mmol), b (1.5 equiv., 0.3 mmol), [Ir(dFCF₃ppy)₂(dtbpy)PF₆] (1 mol%), TMG (70 μL), MeCN (1 mL) and (iBu)₃N (140 μL) under a nitrogen atmosphere irradiated with a 10 W LED for 6 h at room temperature. ^aYields of isolated products are reported. ^b(E)-(2-(Methylsulfonyl)vinyl)benzene was used. ^c4-(2,2-Difluorovinyl)-1,1′-biphenyl was used. ^d4-(3,3,3-Trifluoroprop-1-en-2-yl)-1,1′-biphenyl was used. ^e2-(Methylsulfonyl)benzo[d]thiazole was used.

To demonstrate the applicability of the protocol in late-stage settings, molecular drugs bearing varied functional groups were also modified in good yields. Expectedly, substrates with multiple types of weak C–H bonds produced single regioisomers due to the directed nature of this transformation (51c, 59%). Next, the scope of Michael acceptors in this reaction was investigated. There is not much difference between the overall situation and the above results. We also investigated other addition–elimination reactions with unsaturated sulfone reagents and found that alkylation reactions also proceeded under standard conditions, generating alkene 55c in good yields. The defluorinative cross-coupling with α-trifluoromethyl alkenes and gem-difluoroalkenes was also investigated, affording the gem-difluoroalkene derivate (56c, 83%) and the fluoroalkene derivative in high yields (57c, 79%, E : Z = 3 : 1). Direct α-heteroarylation of tertiary amines with sulfone reagents proved to be effective (58c, 70%). The utility and practicality of this method was demonstrated by the gram-scale preparation of 1c. The use of 5 mmol of 1a could be α-allylated with 1b under our established conditions, and an isolated yield of 1c (71% yield, 1.68 g) comparable to that of the small-scale reaction was obtained (Scheme 4).

Scheme 4 The gram-scale synthesis was successfully performed in a flow reactor.

To rule out that the reaction occurs due to the oxidation of iodine anions, which produces iodine free radicals to extract hydrogen, amines protected by benzoyl groups were tested with the addition of NaI and no generation of target product was detected (Scheme 5a). When TEMPO was added to the optimal reaction system, the reaction was completely suppressed which indicated that the reaction involved a radical process (Scheme 5b). Furthermore, when deuterated substrate d-1e was subjected to the standard conditions, the desired d-37c with a D-atom at the ortho-position was obtained in 38% yield (Scheme 5c).

Scheme 5 Mechanistic studies.

To gain clearer insight into the reaction mechanism, preliminary mechanistic experiments were performed. A kinetic isotope effect (KIE) experiment was first carried out to probe the rate-determining step (Scheme 5d). Under the standard conditions for 1 h, the reaction furnished a mixture of thioether 1e and d-1e in 40% yield in which the ratio of 37c and d-37c was 1.8. These KIE values revealed that hydrogen/deuterium atom abstraction is not a rate-determining step.

Based on the above mechanistic investigations and relevant precedents involving visible-light-induced 1,n-HAT processes and halogen-atom transfer,¹¹ a plausible mechanism for the alkylation reaction is proposed as shown in Scheme 6. Upon blue LED light irradiation, the excited organic photo-catalyst 4CzIPN (*E_red = +1.35 V versus SCE) oxidizes, which, after subsequent deprotonation, furnishes the aminoalkyl radical. This species undergoes XAT with the substrates, generating an electrophilic aryl radical. This radical then initiates an intramolecular hydrogen atom transfer (HAT) from the alkyl-H sites. The formed nucleophilic radical undergoes Giese-type addition to polarized alkenes and subsequent reduction to deliver the desired product.

Scheme 6 Plausible reaction mechanism.

Conclusion

In conclusion, we have developed a visible light-induced α/γ-alkylation or arylation of amines via an aryl radical which is generated by easily installable groups. Compared with previous reports, the present approach offers several advantages: (1) no need for high-energy light, unstable and difficult to install diazonium compounds, highly toxic organotin reagents; (2) α/γ-alkylation or arylation of amines can be achieved separately by regulating the type of protective group; and (3) it has strong practicality: not only can it achieve structural modification of drug molecules and peptides with complex structures, but it can also be used for gram scale synthesis.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data supporting the findings of this study are available within the article and its supplementary information (SI). Supplementary information: experimental procedures and characterization of compounds. See DOI: https://doi.org/10.1039/d5qo01204j.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (No. 22471049), the Science and Technology Plan of Shenzhen (No. JCYJ20230807094408017, JCYJ20220531095016036, and GXWD20220817131550002). W. X. is grateful for the Talent Recruitment Project of Guangdong (No. 2019QN01L753). The project was also supported by the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University.

References

1. T. K. Allred, F. Manoni and P. G. Harran, Exploring the boundaries of “practical”: de novo syntheses of complex natural product-based drug candidates, Chem. Rev., 2017, 117, 11994–12051.
2. (a) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals, Angew. Chem., Int. Ed., 2012, 51, 8960–9009; (b) C. Liu, J. Yuan, M. Gao, S. Tang, W. Li, R. Shi and A. Lei, Oxidative coupling between two hydrocarbons: an update of recent C–H functionalizations, Chem. Rev., 2015, 115, 12138–12204; (c) T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal and S. W. Krska, The medicinal chemist's toolbox for late stage functionalization of drug-like molecules, Chem. Soc. Rev., 2016, 45, 546–576; (d) W. Li, H. Palis, R. Mérindol, J. Majimel, S. Ravaine and E. Duguet, Colloidal molecules and patchy particles: Complementary concepts, synthesis and self-assembly, Chem. Soc. Rev., 2020, 49, 1955–1976.
3. (a) J. Zhang, B. Tiwari, C. Xing, X. Chen and Y. R. Chi, Enantioselective Oxidative Cross–Dehydrogenative Coupling of Tertiary Amines to Aldehydes, Angew. Chem., Int. Ed., 2012, 51, 3649–3652; (b) L. Chu, C. Ohta, Z. Zuo and D. W. MacMillan, Carboxylic acids as a traceless activation group for conjugate additions: a three-step synthesis of (±)-pregabalin, J. Am. Chem. Soc., 2014, 136, 10886–10889; (c) J. Xuan, T. T. Zeng, Z. J. Feng, Q. H. Deng, J. R. Chen, L. Q. Lu, W. J. Xiao and H. Alper, Redox–Neutral α–Allylation of Amines by Combining Palladium Catalysis and Visible–Light Photoredox Catalysis, Angew. Chem., 2015, 127, 1645–1648; (d) M. H. Shaw, V. W. Shurtleff, J. A. Terrett, J. D. Cuthbertson and D. W. MacMillan, Native functionality in triple catalytic cross-coupling: sp3 C–H bonds as latent nucleophiles, Science, 2016, 352, 1304–1308; (e) P. Wang, Z. Yang, T. Wu, C. Xu, Z. Wang and A. Lei, Electrochemical oxidative C (sp3)− H/N− H cross–coupling for N–mannich bases with hydrogen evolution, ChemSusChem, 2019, 12, 3073–3077; (f) M. Sato, H. Azuma, A. Daigaku, S. Sato, K. Takasu, K. Okano and H. Tokuyama, Total Synthesis of (−)–Histrionicotoxin through a Stereoselective Radical Translocation–Cyclization Reaction, Angew. Chem., Int. Ed., 2017, 56, 1087–1091; (g) Y. Kuang, H. Cao, H. Tang, J. Chew, W. Chen, X. Shi and J. Wu, Visible light driven deuteration of formyl C–H and hydridic C (sp 3)–H bonds in feedstock chemicals and pharmaceutical molecules, Chem. Sci., 2020, 11, 8912–8918; (h) Z. Li, P. Ma, Y. Tan, Y. Liu, M. Gao, Y. Zhang, B. Yang, X. Huang, Y. Gao and J. Zhang, Photocatalyst-and transition-metal-free α-allylation of N-aryl tetrahydroisoquinolines mediated by visible light, Green Chem., 2020, 22, 646–650; (i) L. Capaldo, D. Ravelli and M. Fagnoni, Direct photocatalyzed hydrogen atom transfer (HAT) for aliphatic C–H bonds elaboration, Chem. Rev., 2021, 122, 1875–1924; (j) A. Trowbridge, S. M. Walton and M. J. Gaunt, New strategies for the transition-metal catalyzed synthesis of aliphatic amines, Chem. Rev., 2020, 120, 2613–2692.
4. (a) K. S. Chan, M. Wasa, L. Chu, B. N. Laforteza, M. Miura and J.-Q. Yu, Ligand-enabled cross-coupling of C (sp 3)–H bonds with arylboron reagents via Pd(II)/Pd (0) catalysis, Nat. Chem., 2014, 6, 146–150; (b) N. Rodriguez, J. A. Romero-Revilla, M.Á Fernández-Ibáñez and J. C. Carretero, Palladium-catalyzed N-(2-pyridyl) sulfonyl-directed C (sp 3)–H γ-arylation of amino acid derivatives, Chem. Sci., 2013, 4, 175–179; (c) Y. F. Zhang, H. W. Zhao, H. Wang, J. B. Wei and Z. J. Shi, Readily Removable Directing Group Assisted Chemo–and Regioselective C (sp3)-H Activation by Palladium Catalysis, Angew. Chem., Int. Ed., 2015, 54, 13686–13690; (d) M. D. Reddy and E. B. Watkins, Palladium-catalyzed direct arylation of C (sp3)–H bonds of α-cyano aliphatic amides, J. Org. Chem., 2015, 80, 11447–11459; (e) G. He and G. Chen, A practical strategy for the structural diversification of aliphatic scaffolds through the palladium-catalyzed picolinamide-directed remote functionalization of unactivated C (sp3)-H bonds, Angew. Chem., Int. Ed., 2011, 50, 5192–5196; (f) Y. Liu and H. Ge, Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group, Nat. Chem., 2017, 9, 26–32; (g) Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate and J.-Q. Yu, Pd-catalyzed γ-C (sp3)–H arylation of free amines using a transient directing group, J. Am. Chem. Soc., 2016, 138, 14554–14557; (h) Y. Xu, M. C. Young, C. Wang, D. M. Magness and G. Dong, Catalytic C (sp3)− H arylation of free primary amines with an exo directing group generated in situ, Angew. Chem., Int. Ed., 2016, 55, 9084–9087; (i) M. Kapoor, D. Liu and M. C. Young, Carbon dioxide-mediated C (sp3)–H arylation of amine substrates, J. Am. Chem. Soc., 2018, 140, 6818–6822; (j) J. He, M. Wasa, K. S. Chan, Q. Shao and J.-Q. Yu, Palladium-catalyzed transformations of alkyl C–H bonds, Chem. Rev., 2017, 117, 8754–8786.
5. W. Guo, Q. Wang and J. Zhu, Visible light photoredox-catalysed remote C–H functionalisation enabled by 1, 5-hydrogen atom transfer (1, 5-HAT), Chem. Soc. Rev., 2021, 50, 7359–7377.
6. (a) D. Hey and D. Turpin, Abnormal reactions of 2-amino-N-methylbenzanilides containing ortho-substituents, J. Chem. Soc., 1954, 2471–2481; (b) A. Lewin, A. Dinwoodie and T. Cohen, 1, 5-hydrogen transfer during diazonium ion decomposition—IV: The copper catalyzed reaction. A Case of hydrogen atom or hydride ion transfer in the same system, Tetrahedron, 1966, 22, 1527–1537; (c) F.-Q. Huang, X. Dong, L.-W. Qi and B. Zhang, Visible-light photocatalytic α-amino C (sp3)–H activation through radical translocation: a novel and metal-free approach to α-alkoxybenzamides, Tetrahedron Lett., 2016, 57, 1600–1604.
7. (a) D. P. Curran and J. Xu, o-Bromo-p-methoxyphenyl ethers. Protecting/radical translocating (PRT) groups that generate radicals from C− H bonds β to oxygen atoms, J. Am. Chem. Soc., 1996, 118, 3142–3147; (b) D. P. Curran and H. Yu, New applications of 1, 5-hydrogen atom transfer reactions: self-oxidizing protecting groups, Synthesis, 1992, 123–127; (c) V. Snieckus, J. Cuevas, C. Sloan, H. Liu and D. P. Curran, Intramolecular. alpha.-amidoyl-to-aryl 1, 5-hydrogen atom transfer reactions. Heteroannulation and. alpha.-nitrogen functionalization by radical translocation, J. Am. Chem. Soc., 1990, 112, 896–898; (d) D. P. Curran and H. Liu, Radical translocation reactions across amides. 1, 5-Hydrogen-transfer reactions of o-iodobenzamides and N-(o-iodobenzyl) amides, J. Chem. Soc., Perkin Trans. 1, 1994, 1377–1393; (e) D. P. Curran, A. C. Abraham and H. Liu, Radical translocation reactions of o-iodoanilides: the use of carbon-hydrogen bonds as precursors of radicals adjacent to carbonyl groups, J. Org. Chem., 1991, 56, 4335–4337.
8. (a) W. Liu, J. Li, C. Y. Huang and C. J. Li, Aromatic Chemistry in the Excited State: Facilitating Metal–Free Substitutions and Cross–Couplings, Angew. Chem., 2020, 132, 1802–1812; (b) M. De Carolis, S. Protti, M. Fagnoni and A. Albini, Metal–Free Cross–Coupling Reactions of Aryl Sulfonates and Phosphates through Photoheterolysis of Aryl–Oxygen Bonds, Angew. Chem., Int. Ed., 2005, 44, 1232–1236; (c) S. Protti, M. Fagnoni, M. Mella and A. Albini, Aryl cations from aromatic halides. Photogeneration and reactivity of 4-hydroxy (methoxy) phenyl cation, J. Org. Chem., 2004, 69, 3465–3473; (d) M. Fagnoni and A. Albini, Arylation reactions: the photo-SN1 path via phenyl cation as an alternative to metal catalysis, Acc. Chem. Res., 2005, 38, 713–721; (e) V. Dichiarante, M. Fagnoni and A. Albini, Metal–Free Synthesis of Sterically Crowded Biphenyls by Direct Ar-H Substitution in Alkyl Benzenes, Angew. Chem., 2007, 119, 6615–6618; (f) S. Protti, M. Fagnoni and A. Albini, Photo-cross-coupling reaction of electron-rich aryl chlorides and aryl esters with alkynes: a metal-free alkynylation, Angew. Chem., Int. Ed., 2005, 5675–5678.
9. (a) S. Sarkar, K. P. S. Cheung and V. Gevorgyan, C–H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals, Chem. Sci., 2020, 11, 12974–12993; (b) A.-F. Voica, A. Mendoza, W. R. Gutekunst, J. O. Fraga and P. S. Baran, Guided desaturation of unactivated aliphatics, Nat. Chem., 2012, 4, 629–635; (c) K. A. Hollister, E. S. Conner, M. L. Spell, K. Deveaux, L. Maneval, M. W. Beal and J. R. Ragains, Remote Hydroxylation through Radical Translocation and Polar Crossover, Angew. Chem., Int. Ed., 2015, 54, 7837–7841; (d) M. Parasram, P. Chuentragool, D. Sarkar and V. Gevorgyan, Photoinduced formation of hybrid aryl Pd-radical species capable of 1, 5-HAT: selective catalytic oxidation of silyl ethers into silyl enol ethers, J. Am. Chem. Soc., 2016, 138, 6340–6343; (e) P. Chuentragool, M. Parasram, Y. Shi and V. Gevorgyan, General, mild, and selective method for desaturation of aliphatic amines, Gevorgyan, J. Am. Chem. Soc., 2018, 140, 2465–2468; (f) F. W. Friese, C. Mück-Lichtenfeld and A. Studer, Remote C− H functionalization using radical translocating arylating groups, Nat. Commun., 2018, 9, 2808; (g) N. Radhoff and A. Studer, Functionalization of α–C (sp3)− H Bonds in Amides Using Radical Translocating Arylating Groups, Angew. Chem., Int. Ed., 2021, 60, 3561–3565; (h) C. Wang, L. M. Azofra, P. Dam, M. Sebek, N. Steinfeldt, J. Rabeah and O. El-Sepelgy, Catalytic desaturation of aliphatic amides and imides enabled by excited-state base-metal catalysis, ACS. Catal., 2022, 12, 8868–8876; (i) R. Guo, H. Xiao, S. Li, Y. Luo, J. Bai, M. Zhang, Y. Guo, X. Qi and G. Zhang, Photoinduced copper–catalyzed asymmetric C (sp3)− H alkynylation of cyclic amines by intramolecular 1, 5−hydrogen atom transfer, Angew. Chem., Int. Ed., 2022, 61, e202208232; (j) W.-L. Yu, Z.-G. Ren, K.-X. Ma, H.-Q. Yang, J.-J. Yang, H. Zheng, W. Wu and P.-F. Xu, Cobalt-catalyzed chemoselective dehydrogenation through radical translocation under visible light, Chem. Sci., 2022, 13, 7947–7954; (k) S. Sarkar, S. Wagulde, X. Jia and V. Gevorgyan, General and selective metal-free radical α-C–H borylation of aliphatic amines, Chem, 2022, 8, 3096–3108; (l) J. Wang, Q. Xie, G. Gao, G. Wei, X. Wei, X. Chen, D. Zhang, H. Li and B. Huang, Visible-light-mediated synthesis of polysubstituted pyrroles via C_Ar–I reduction triggered 1,5-hydrogen atom transfer process, Org. Chem. Front., 2024, 11, 4522–4528; (m) J. Wang, Q. Xie, G. Gao, H. Li, W. Lu, X. Cai, X. Chen and B. Huang, Selective N-α-C–H alkylation of cyclic tertiary amides via visible-light-mediated 1,5-hydrogen atom transfer, Org. Chem. Front., 2023, 10, 4394–4399; (n) Z. Li, W. Yan, X. Zhou, C. Yang, L. Guo and W. Xia, Multicomponent synthesis of unsymmetrical 1,2-diamines via photo-induced carbonyl alkylative amination, Org. Chem. Front., 2025, 12, 4946–4955; (o) Z. Lei, W. Zhang and J. Wu, Photocatalytic Hydrogen Atom Transfer-Induced Arbuzov-Type α-C(sp³)–H Phosphonylation of Aliphatic Amines, ACS Catal., 2023, 13, 16105–16113; (p) V. Srinivasu, S. Pattanaik and D. Sureshkumar, Photoredox cross-dehydrogenative C(sp²)–C(sp³) coupling of heteroarenes with secondary amines through 1,5-HAT, Chem. Commun., 2024, 60, 9757–9760; (q) J. Wang, Q. Xie, G. Gao, G. Wei, X. Wei, X. Chen, D. Zhang, H. Li and B. Huang, Visible-light-mediated synthesis of polysubstituted pyrroles via C_Ar–I reduction triggered 1,5-hydrogen atom transfer process, Org. Chem. Front., 2024, 11, 4522–4528; (r) V. K. Simhadri, R. Sur and V. R. Yatham, Photoinduced Remote Selective C(sp³)–H Alkylation Mediated by Cesium Formate, Eur. J. Org. Chem., 2024, e202400490; (s) M. G. Pizzio, E. G. Mata, P. Dauban and T. Saget, Photocatalytic C–H Functionalization of Nitrogen Heterocycles Mediated by a Redox Active Protecting Group, Eur. J. Org. Chem., 2023, e202300616.
10. C. Chatgilialoglu, C. Ferreri, Y. Landais and V. I. Timokhin, Thirty years of (TMS) 3SiH: a milestone in radical-based synthetic chemistry, Chem. Rev., 2018, 118, 6516–6572.
11. (a) T. Constantin, M. Zanini, A. Regni, N. S. Sheikh, F. Juliá and D. Leonori, Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides, Science, 2020, 367, 1021–1026; (b) A. Yada, W. Liao, Y. Sato and M. Murakami, Buttressing salicylaldehydes: a multipurpose directing group for C (sp3)− H bond activation, Angew. Chem., Int. Ed., 2017, 56, 1073–1076; (c) F. Juliá, T. Constantin and D. Leonori, Applications of halogen-atom transfer (XAT) for the generation of carbon radicals in synthetic photochemistry and photocatalysis, Chem. Rev., 2021, 122, 2292–2352.

---