Catalyst-free C–H methylation of heteroarenes enabled by electron donor–acceptor complex photoactivation

Abstract

An efficient, additive- and catalyst-free, visible-light-driven radical C–H methylation of heteroarenes (including quinoxalinones, pyrazinones, quinolinones and coumarins) utilizing readily available methylamines as the methyl source has been developed. The transformation possesses the advantages of operational simplicity, mild reaction conditions and broad substrate scope. Mechanistic studies disclosed that a photoactive electron donor–acceptor (EDA) complex between methylamines and heteroarenes is crucial to this transformation.

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Introduction

Methylation is an important modification in biological systems and medicinal chemistry.¹ In biology, histone and DNA methylation are crucial to gene expression.² In medicinal chemistry, the transformation achieved by introducing a methyl group could fundamentally improve metabolic stability, hydrophobic interactions and conformational effects, leading to a potency increase of 100–1000 fold for drug candidates, which is known as the “Magic Methyl Effect,” as demonstrated by Cernak.³ For instance, during a structure–activity relationship (SAR) study on the antineoplastic medication tazemetostat, the discovery team explored the substitution of C–H bonds with C–CH₃ bonds at four distinct sites of a lead molecule. Observations revealed a remarkable increase in potency of over 100 000 times.^3d Additionally, the methyl functional group is highly versatile in organic synthesis and can be easily converted to a broad range of useful groups such as aldehydes, hydroxymethyls, cyanides and carboxylic acids.⁴ As a result, a number of synthetic strategies have been devoted to methylation reactions. In particular, installing a methyl group on heterocyclic molecules has been greatly valued and developed since they are considered as privileged structures in drug discovery.⁵

Cross-coupling reactions catalyzed by transition metals have consistently been one of the most adaptable and dependable methods in organic synthesis.⁶ Conventional approaches for the methylation of heterocycles commonly rely on transition-metal-catalyzed cross-coupling reactions between organometallic reagents and heterocycles (Scheme 1a).⁷ However, the unavoidable use of unstable, toxic methylating reagents and high reaction temperatures could limit their applications. Nowadays, visible-light-driven photocatalysis has become a synthetically valuable tool for organic transformations due to its operational simplicity, environmental friendliness and mild reaction conditions.⁸ Meanwhile, visible-light-mediated methylation of heterocycles employing various methyl radical precursors such as CH₃OTs, CH₃B(OH)₂, and CH₃B(O₂Ar)Li has emerged (Scheme 1b).⁹ However, these photocatalytic reactions commonly proceed under the catalysis of photosensitizers such as expensive organic dyes (pyrylium and acridinium salt) and precious metals (Ir- and Ru-complexes). Recently, visible-light-induced photocatalysis without additional photocatalysts has received considerable attention. Among these, the photochemistry of the electron-donor–acceptor (EDA) complex has been of particular interest to synthetic chemists.¹⁰

Scheme 1 C–H methylation of heterocycles.

As part of our ongoing research interest in developing efficient, green and valuable C–H functionalization reactions,¹¹ we disclose herein a visible-light-induced methylation of heteroarenes with methylamines (Scheme 1c). It is worth noting that oxidant and photoredox catalysts were not required during the reaction process, and this transformation proceeded under mild reaction conditions via the formation of an electron donor–acceptor (EDA) complex between two reactants, heteroarenes and methylamines, providing a novel approach for the methylation of heteroarene derivatives.

Results and discussion

To verify the feasibility of the strategy, we began our investigations by using 1-methylquinoxalin-2(1H)-one 1a and N,N,N′,N′-tetramethylethylenediamine (TMEDA) 2a as substrates (Table 1). Initially, CH₃CN was chosen as the solvent, and the reaction was irradiated with a 400 nm LED (10 W) at room temperature under an N₂ atmosphere with K₂CO₃ as the base. However, the desired product 3a was obtained in only 40% yield (Table 1, entry 1). Next, the performance of various methylamines as methyl sources was evaluated. N,N,N’-Trimethylethane-1,2-diamine 2b, N,N,N′,N’-tetramethylmethanediamine 2c, and methylamines bearing aromatic rings, and carboxyl, hydroxyl, cyano, amino, and ester groups (2d–2i), all exhibit lower reactivity. Furthermore, betaine 2j with three methyl groups was ineffective. Subsequently, various solvents of different polarities including DCE, DMA, THF, EtOH, EtOAc, CH₃CN and acetone were screened, and the results showed that DCE was the optimal solvent (Table 1, entries 2–8). To our delight, it was observed that the chemical yield of 3a was significantly promoted when an appropriate amount of water was added to this reaction system (Table 1, entry 9). The mixed solvent of DCE/H₂O at different ratios was tested to further clarify the significance of water in promoting this transformation, and the yield of 3a could be increased to 76% when DCE/H₂O (4 : 1) was employed as the solvent (Table 1, entries 10 and 11). It should be pointed out that employing other Brønsted bases such as Li₂CO₃, Cs₂CO₃, K₃PO₄ and K₂HPO₄ instead of K₂CO₃ caused the reaction yield to diminish obviously (Table 1, entries 12–15). The light source is also a crucial parameter in this model irradiation-induced reaction. Using purple LEDs with wavelengths of both 380 nm and 390 nm resulted in a reduced yield (Table 1, entries 16 and 17). Other irradiation sources with wavelengths of 410 nm, 420 nm, 430 nm and 460 nm were also investigated, and the results showed that the desired 3a could be obtained with an optimal yield of 81% when the reaction was conducted under irradiation at 410 nm (Table 1, entries 18–21). The reaction yield decreased when the transformation was performed under an air atmosphere (Table 1, entry 22). Finally, control studies demonstrated the necessity of light (Table 1, entry 23).

Table 1 Optimization of the reaction conditions^a

Entry	Light source	Solvent	Base	Yield^b (%)
a Reaction conditions: 1a (0.30 mmol), 2a (0.90 mmol), solvent (2.0 mL), r.t., 10 W LED, N2 atmosphere, 16 h. b Isolated yield. c Under light irradiation (10 W) in air for 16 h. N.R. = no reaction.
1	400 nm	CH3CN	K2CO3	40
2	400 nm	DCE	K2CO3	60
3	400 nm	DMA	K2CO3	55
4	400 nm	THF	K2CO3	Trace
5	400 nm	EtOH	K2CO3	Trace
6	400 nm	EtOAc	K2CO3	36
7	400 nm	H2O	K2CO3	26
8	400 nm	Acetone	K2CO3	52
9	400 nm	DCE : H2O = 8 : 1	K2CO3	73
10	400 nm	DCE : H2O = 4 : 1	K2CO3	76
11	400 nm	DCE : H2O = 2 : 1	K2CO3	72
12	400 nm	DCE : H2O = 4 : 1	Li2CO3	56
13	400 nm	DCE : H2O = 4 : 1	Cs2CO3	59
14	400 nm	DCE : H2O = 4 : 1	K3PO4	62
15	400 nm	DCE : H2O = 4 : 1	K2HPO4	53
16	380 nm	DCE : H2O = 4 : 1	K2CO3	39
17	390 nm	DCE : H2O = 4 : 1	K2CO3	52
18	410 nm	DCE : H 2 O = 4 : 1	K 2 CO 3	81
19	420 nm	DCE : H2O = 4 : 1	K2CO3	68
20	430 nm	DCE : H2O = 4 : 1	K2CO3	43
21	460 nm	DCE : H2O = 4 : 1	K2CO3	N.R.
22^c	410 nm	DCE : H2O = 4 : 1	K2CO3	57
23	In the dark	DCE : H2O = 4 : 1	K2CO3	N.R.

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With the optimized reaction conditions established, the substrate scope of quinoxalinones was explored (Scheme 2). N-Alkylated quinoxalinones 1a–1d and N-benzylated quinoxalinones 1e–1k were readily methylated with 2a to afford the expected products 3a–3k in satisfactory yields (48–85%). Additionally, quinoxalin-2(1H)-one 1l was also tolerated in this transformation, furnishing the corresponding products in 58% yields. In addition, various electron-withdrawing substitution patterns on the benzene ring of 1-methylquinoxalin-2(1H)-one were also evaluated and proven to be suitable substrates, delivering the target products 3m–3q in 45–57% yields. The reaction also proceeded smoothly with N-arylated quinoxalinones 1r–1w, providing the methylated products 3r–3w in moderate yields (33–55%). Apart from the above methylation of quinoxalinones, other alkylamines were further evaluated. In the case of ethylation, pentylation and hexylation, the desired products 3x (74%), 3y (65%) and 3z (60%) were obtained in satisfactory yields.

Scheme 2 Substrate scope for methylation and alkylation of quinoxalinones. Reaction conditions: quinoxalinones 1 (0.3 mmol), tetraalkylethylenediamines 2 (0.9 mmol) and K₂CO₃ (0.9 mmol) in 2 mL of DCM/H₂O (4 : 1) at room temperature and illumination at 410 nm (10 W) under a N₂ atmosphere for 16 h. Isolated yield.

Encouraged by the above results, we turned our attention to expanding the substrate scope of this visible-light-induced transformation to other valuable heterocycles employing our novel methylation strategy (Scheme 3). Under slightly modified reaction conditions, a wide range of pyrazinones were compatible with this process. First, N-benzylated and N-arylated pyrazinones 4a–4d were prepared and subjected to the standard conditions, providing the corresponding C3-methylated pyrazinones 7a–7d in 51–72%. Moreover, the methylation of N-alkylated-5-phenylpyrazinones 4e–4r also took place under these reaction conditions. It is noteworthy that N-alkyl-5-phenylpyrazinones (4i–4k) containing halide and nitro groups provided relatively low yields. In addition, C5-arylated pyrazinones containing either electron-withdrawing or electron-donating groups on the arene ring could also undergo the photo-induced transformation well, providing the target products 7l–7p in 36–55% yields. Then, tri-substituted pyrazinone 4q was shown to be suitable for the transformation, giving product 7q in 51% yield. Furthermore, N-methylated 5-phenylquinoxalinone 4r was subjected to ethylation, affording the desired product 7r in 56% yield. Afterwards, the scope of the reaction with respect to quinolinones was investigated. Obviously, a diverse array of quinolinones containing different sterically and electronically varied groups such as hydrogen, fluoro, chloro, methoxy, ester, and methyl groups at the benzene ring reacted smoothly under our reaction conditions, delivering the corresponding products 8a–8f in 39–73% yields. To our delight, when 1,4-dimethylquinolin-2(1H)-one 5g and 1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one 5h were used as substrates, the reaction proceeded readily, furnishing the expected products in 46% and 61% yields, respectively. To further broaden the substrate scope, quinolinones bearing N-protecting groups such as cyclopropane methyl, cyclopenta methyl and n-hexyl groups were also explored, producing the corresponding methylated products 8i–8k in good yields ranging from 55–80%. To highlight the synthetic value of the developed method, the scope of coumarins 6a–6l was further explored. Substrates bearing varied functional groups such as alkyl, alkoxy, fluoro, chloro, and ester groups on the benzene ring scaffold were compatible by using N,N-dimethylglycine 2e as a methyl source, delivering products 9a–9k in 39–77% yields. Moreover, 3H-naphtho[2,1-b]pyran-3-one 6l could also serve as a substrate to furnish product 9l in 48% yield.

Scheme 3 Substrate scope for methylation and alkylation of heteroarenes. ^a Reaction conditions: 4–5 (0.3 mmol), tetramethylethylenediamine 2a (0.9 mmol) and K₃PO₄ (0.9 mmol) in 2 mL of DMA at room temperature and illumination at 410 nm (10 W) under a N₂ atmosphere for 16 h. ^b Tetraethylethylethylenediamine was used instead of 2a. ^c Reaction conditions: 6 (0.3 mmol), N,N-dimethylglycine 2e (0.9 mmol) and K₃PO₄ (0.9 mmol) in 2 mL of DMA/H₂O (1 : 1) at room temperature and illumination at 410 nm (10 W) under a N₂ atmosphere for 20 h. Isolated yield.

The practicality and utility of this visible-light-driven methylation of heteroarenes was initially demonstrated by the scaled-up preparation of 3a (Scheme 4A). 3 mmol of 1a could be methylated with TMEDA under the established conditions, and good yields (75% yield, 391 mg) comparable to those obtained using the small-scale reaction could still be obtained. In addition, the application of this synthetic method was further exemplified by the construction of a high-affinity BRPF (bromodomain and PHD finger-containing) inhibitor. Intermediate 5a was readily methylated with 2a to provide 8a in 67% yield under our standard reaction conditions. After nitration with KNO₃ in conc H₂SO₄, intermediate 8l was obtained in 80% yield. Reduction of the amino group of 8l afforded aminoquinoxaline 10 in 82% yield. Finally, a nucleophilic substitution reaction between 10 and 4-cyanobenzenesulfonyl chloride provided the desired BRPF inhibitor in 50% yield. Besides, 5l has also been tested for the synthesis of the BRPF inhibitor and the nitro group on the phenyl skeleton completely weakened the reactivity. Additional research was conducted on the utilization of this protocol for the development of bioactive molecules and pharmaceuticals of high value. The synthesis of an angiotensin II receptor antagonist can be effectively achieved by photo-induced methylation. Under standard conditions, the nitrogen-substituted ester of 6-bromoquinoxalin-2(1H)-one 12 can be easily transformed into the methylation product 13. Product 13 can then be reduced with hydrazine hydrate, resulting in the formation of the c-Met kinase inhibitor.¹²

Scheme 4 ^a  Gram-scale reaction and synthesis of the bromodomain inhibitor. Reagents and conditions for B: (a) TMEDA (3.0 equiv.), K₃PO₄ (3.0 equiv.), DMA, N₂ atmosphere, hv (410 nm), rt, 16 h; (b) conc. H₂SO₄, KNO₃ (1.05 equiv.), rt, 4 h; (c) Fe (8.0 equiv.), NH₄Cl (5.0 equiv.), EtOH, 60 °C, 4 h; and (d) 4-cyanobenzenesulfonyl chloride (1.0 equiv.), pyridine, rt, 12 h.

To understand this transformation, we performed some control experiments (Scheme 5a). When the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy was added to the model reaction, the transformation was completely suppressed. Meanwhile, the addition of 2,6-ditert-butyl-4-methyl-phenol or 1,1-diphenylethylene led to a dramatic decrease in yield. The corresponding radical adducts were clearly identified by HRMS, indicating that the reaction mechanism involved a radical process. In order to further elucidate the mechanism of this photoinduced methylation reaction, we measured the UV-visible spectra of various combinations including 1a, 2a, and K₂CO₃ to explore the formation of the proposed EDA complex. After mixing the two substrates 1a and 2a, the solution developed a yellowish color, and an obvious red shift in the absorption could be observed in the visible light region, indicating the formation of a visible-light-active EDA complex (Scheme 5b). Moreover, NMR titration experiments were performed to investigate the interactions of 1a and 2a, and the results suggest clearly that the EDA complex is indeed formed (Scheme 5c).

Scheme 5 Mechanistic studies.

In accordance with these mechanism experiments and previous reports,¹³ a mechanism has been proposed (Scheme 6). Initially, 1-methylquinoxalin-2(1H)-one 1a reacts with TMEDA 2a to generate an EDA complex. Upon visible-light irradiation, a single electron is then transferred within the EDA complex, simultaneously generating the nitrogen-containing heterocyclic radical anion A and the amino radical cation B. Subsequently, B experiences an isomerization process to give the α-amino radical C. The coupling of radical C with the radical anion A generates the key intermediate D, which undergoes subsequent intramolecular nucleophilic substitution to form the ternary ring product E. It is worth noting that the formation of intermediate D was confirmed by mass analysis (see the ESI†). The cleavage of the α-C–H bond could be facilitated by bases such as TMEDA or K₂CO₃, followed by intramolecular electron transfer to generate the carbanion intermediate F. Presumably, a barrierless protonation of intermediate F occurred, leading to the observed C3-methylated quinoxalinone 3a.

Scheme 6 Proposed mechanism.

Conclusions

In conclusion, we have presented a visible-light-induced direct C–H methylation of heterocycles (including quinoxalinones, pyrazinones, quinolinones and coumarins) with methylamines via EDA complexes. This mild methylation can proceed without any transition-metal catalysts, photocatalysts, or additional oxidants. It is noteworthy that apart from the methylation, other alkylations such as ethylation, pentylation and hexylation also proceeded smoothly under the reaction conditions. We are confident that this benign protocol is a meaningful alternative to existing strategies for the construction of heterocycles of pharmaceutical and biological value.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Introducing Talents of Huzhou University (RK23087) and the Natural Science Foundation of Huzhou City (2022YZ23). We are also grateful to the Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province for technical support.

References

1. (a) N. A. McGrath, M. Brichacek and J. T. Njardarson, A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives, J. Chem. Educ., 2010, 87, 1348–1349; (b) T. J. Ritchie, S. J. F. Macdonald and S. D. Pickett, Insights into the Impact of N- and O-methylation on Aqueous Solubility and Lipophilicity Using Matched Molecular Pair Analysis, MedChemComm, 2015, 6, 1787–1797.
2. (a) J. S. Choy, S. Wei, J. Y. Lee, S. Tan, S. Chu and T.-H. Lee, DNA Methylation Increases Nucleosome Compaction and Rigidity, J. Am. Chem. Soc., 2010, 132, 1782–1783; (b) Y.-J. Yang, H.-L. Dong, X.-W. Qiang, H. Fu, E.-C. Zhou, C. Zhang, L. Yin, X.-F. Chen, F.-C. Jia, L. Dai, Z.-J. Tan and X.-H. Zhang, Cytosine Methylation Enhances DNA Condensation Revealed by Equilibrium Measurements Using Magnetic Tweezers, J. Am. Chem. Soc., 2020, 142, 9203–9209.
3. (a) E. J. Barreiro, A. E. Kümmerle and C. A. M. Fraga, The Methylation Effect in Medicinal Chemistry, Chem. Rev., 2011, 111, 5215–5246; (b) H. Schönherr and T. Cernak, Profound Methyl Effects in Drug Discovery and a Call for New C-H Methylation Reactions, Angew. Chem., Int. Ed., 2013, 52, 12256–12267; (c) S. Sun and J. Fu, Methyl-Containing Pharmaceuticals: Methylation in Drug Design, Bioorg. Med. Chem. Lett., 2018, 28, 3283–3289; (d) K. W. Kuntz, J. E. Campbell, H. Keilhack, R. M. Pollock, S. K. Knutson, M. P. Scott, V. M. Richon, C. J. Sneeringer, T. J. Wigle, C. J. Allain, C. R. Majer, M. P. Moyer, R. A. Copeland and R. Chesworth, The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat, J. Med. Chem., 2016, 59, 1556–1564.
4. (a) S. Das, T. Bhowmick, T. Punniyamurthy, D. Dey, J. Nath and M. K. Chaudhuri, Molybdenum(VI)-Peroxo Complex Catalyzed Oxidation of Alkylbenzenes with Hydrogen Peroxide, Tetrahedron Lett., 2003, 44, 4915–4917; (b) J. Liu, H.-X. Zheng, C.-Z. Yao, B.-F. Sun and Y.-B. Kang, Pharmaceutical-Oriented Selective Synthesis of Mononitriles and Dinitriles Directly from Methyl(hetero)arenes: Access to Chiral Nitriles and Citalopram, J. Am. Chem. Soc., 2016, 138, 3294–3297; (c) A. Potthast, T. Rosenau, C.-L. Chen and J. S. Gratzl, Selective Enzymatic Oxidation of Aromatic Methyl Groups to Aldehydes, J. Org. Chem., 1995, 60, 4320–4321; (d) P. Mohammadpour and E. Safaei, Catalytic C-H Aerobic and Oxidant-Induced Oxidation of Alkylbenzenes (Including Toluene Derivatives) over VO²⁺ Immobilized on Core-Shell Fe₃O₄@SiO₂ at Room Temperature in Water, RSC Adv., 2020, 10, 23543–23553.
5. (a) J. Gui, Q. Zhou, C.-M. Pan, Y. Yabe, A. C. Burns, M. R. Collins, M. A. Ornelas, Y. Ishihara and P. S. Baran, C-H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase, J. Am. Chem. Soc., 2014, 136, 4853–4856; (b) P. L. Norcott, C. L. Hammill, B. B. Noble, J. C. Robertson, A. Olding, A. C. Bissember and M. L. Coote, TEMPO-Me: An Electrochemically Activated Methylating Agent, J. Am. Chem. Soc., 2019, 141, 15450–15455; (c) J. Kim, D. Kim and S. Chang, Merging Two Functions in a Single Rh Catalyst System: Bimodular Conjugate for Light-Induced Oxidative Coupling, J. Am. Chem. Soc., 2020, 142, 19052–19057; (d) Z.-X. He, Y.-P. Gong, X. Zhang, L.-Y. Ma and W. Zhao, Pyridazine as a Privileged Structure: An Updated Review on Anticancer Activity of Pyridazine Containing Bioactive Molecules, Eur. J. Med. Chem., 2021, 209, 112946; (e) G. Sivakumar, R. Kumar, V. Yadav, V. Gupta and E. Balaraman, Multi-Functionality of Methanol in Sustainable Catalysis: Beyond Methanol Economy, ACS Catal., 2023, 13, 15013–15053; (f) L. Petitpoisson, A. Pichette and J. Alsarraf, Towards Better Syntheses of Partially Methylated Carbohydrates?, Org. Chem. Front., 2022, 9, 5414–5425; (g) D. Aynetdinova, M. C. Callens, H. B. Hicks, C. Y. X. Poh, B. D. A. Shennan, A. M. Boyd, Z. H. Lim, J. A. Leitch and D. J. Dixon, Installing the “Magic Methyl” – C-H Methylation in Synthesis, Chem. Soc. Rev., 2021, 50, 5517–5563; (h) Y. Chen, Recent Advances in Methylation: A Guide for Selecting Methylation Reagents, Chem. – Eur. J., 2019, 25, 3405–3439.
6. (a) X. Yan, D. Yu, H. Liu and P. Huang, Intramolecular Carboamination of Aminodienes to N-Heterocycles via C-N Bond Activation, Angew. Chem., Int. Ed., 2024, 63, e202316563; (b) Q. Wang, Y. Su, L. Li and H. Huang, Transition-Metal Catalysed C-N Bond Activation, Chem. Soc. Rev., 2016, 45, 1257–1272; (c) S. Guo, B. Qian, Y. Xie, C. Xia and H. Huang, Copper-Catalyzed Oxidative Amination of Benzoxazoles via C-H and C-N Bond Activation: A New Strategy for Using Tertiary Amines as Nitrogen Group Sources, Org. Lett., 2011, 13, 522–525.
7. (a) T. Kubo and N. Chatani, Dicumyl Peroxide as a Methylating Reagent in the Ni-Catalyzed Methylation of Ortho C-H Bonds in Aromatic Amides, Org. Lett., 2016, 18, 1698–1701; (b) T. Uemura, M. Yamaguchi and N. Chatani, Phenyltrimethylammonium Salts as Methylation Reagents in the Nickel-Catalyzed Methylation of C-H bonds, Angew. Chem., Int. Ed., 2016, 55, 3162–3165; (c) J. Wang, J. Zhao and H. Gong, Nickel-Catalyzed Methylation of Aryl Halides/Tosylates with Methyl Tosylate, Chem. Commun., 2017, 53, 10180–10183; (d) X.-Y. Chen and E. J. Sorensen, Pd-Catalyzed, Ortho C−H Methylation and Fluorination of Benzaldehydes Using Orthanilic Acids as Transient Directing Groups, J. Am. Chem. Soc., 2018, 140, 2789–2792; (e) Z.-T. He, H. Li, A. M. Haydl, G. T. Whiteker and J. F. Hartwig, Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Arylboronic Esters, J. Am. Chem. Soc., 2018, 140, 17197–17202; (f) B. Yao, R.-J. Song, Y. Liu, Y.-X. Xie, J.-H. Li, M.-K. Wang, R.-Y. Tang, X.-G. Zhang and C.-L. Deng, Palladium-Catalyzed C-H Oxidation of Isoquinoline N-Oxides: Selective Alkylation with Dialkyl Sulfoxides and Halogenation with Dihalo Sulfoxides, Adv. Synth. Catal., 2012, 354, 1890–1896; (g) B. Feng, Y. Yang and J. You, A Methylation Platform of Unconventional Inert Aryl Electrophiles: Trimethylboroxine as a Universal Methylating Reagent, Chem. Sci., 2020, 11, 6031–6035.
8. (a) B. Sun, J. Wang, S. Zhou, J. Xu, X. Zhuang, Z. Meng, Y. Xu, Z. Zhang and C. Jin, Decatungstate/Cobalt Dual Catalyzed Dehydrogenation of Ketones Enabled by Polarity-Matched Site-Selective Activation, ACS Catal., 2024, 14, 11138–11146; (b) P. Huang, C. Lv, H. Song, C. Wang, J. Du, J. Li, B. Sun and C. Jin, An in Situ Generated Proton Initiated Aromatic Fluoroalkylation via Electron Donor-Acceptor Complex Photoactivation, Green Chem., 2024, 26, 7198–7205; (c) P. Huang, Y. Xu, H. Song, J. Wang, J. Wang, J. Li, B. Sun and C. Jin, Selective C(sp³)-H Bond Aerobic Oxidation Enabled by a π-Conjugated Small Molecule-Oxygen Charge Transfer State, Green Chem., 2024, 26, 9241–9249; (d) S. K. Pagire, T. Föll and O. Reiser, Shining Visible Light on Vinyl Halides: Expanding the Horizons of Photocatalysis, Acc. Chem. Res., 2020, 53, 782–791; (e) S. Crespi and M. Fagnoni, Generation of Alkyl Radicals: From the Tyranny of Tin to the Photon Democracy, Chem. Rev., 2020, 120, 9790–9833.
9. (a) G.-X. Li, C. A. Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu and G. Chen, Photoredox-Mediated Minisci C-H Alkylation of N-Heteroarenes Using Boronic Acids and Hypervalent Iodine, Chem. Sci., 2016, 7, 6407–6412; (b) C. Jin, Z. Yan, B. Sun and J. Yang, Visible-Light-Induced Regioselective Alkylation of Coumarins via Decarboxylative Coupling with N-Hydroxyphthalimide Esters, Org. Lett., 2019, 21, 2064–2068; (c) T. McCallum, S. P. Pitre, M. Morin, J. C. Scaiano and L. Barriault, The Photochemical Alkylation and Reduction of Heteroarenes, Chem. Sci., 2017, 8, 7412–7418; (d) W.-M. Zhang, J.-J. Dai, J. Xu and H.-J. Xu, Visible-Light-Induced C2 Alkylation of Pyridine N-Oxides, J. Org. Chem., 2017, 82, 2059–2066; (e) Y. Sato, K. Nakamura, Y. Sumida, D. Hashizume, T. Hosoya and H. Ohmiya, Generation of Alkyl Radical through Direct Excitation of Boracene-Based Alkylborate, J. Am. Chem. Soc., 2020, 142, 9938–9943.
10. (a) M. O. Konev, L. Cardinale and A. J. Wangelin, Catalyst-Free N-Deoxygenation by Photoexcitation of Hantzsch Ester, Org. Lett., 2020, 22, 1316–1320; (b) B. Sun, X. Shi, X. Zhuang, P. Huang, R. Shi, R. Zhu and C. Jin, Photoinduced EDA Complexes Enabled Radical Tandem Cyclization/Arylation of Unactivated Alkene with 2-Amino-1,4-Naphthoquinones, Org. Lett., 2021, 23, 1862–1867; (c) Z. Li, S. Wang, Y. Huo, B. Wang, J. Yan and Q. Guo, Visible Light-Driven Fluoroalkylthiocyanation of Alkenes via Electron Donor-Acceptor Complexes, Org. Chem. Front., 2021, 8, 3076–3081; (d) G. E. M. Crisenza, D. Mazzarella and P. Melchiorre, Synthetic Methods Driven by the Photoactivity of Electron-Donor Acceptor Complexes, J. Am. Chem. Soc., 2020, 142, 5461–5476; (e) Q. Zhou, C. G. Sun, X. Liu, X. Li, Z. Shao, K. Tan and Y. Shen, Electron Donor–Acceptor Complex-Catalyzed Photoredox Reactions Mediated by DIPEA and Inorganic Carbonates, Org. Chem. Front., 2022, 9, 5264–5271; (f) Z.-Z. Zhou, X.-F. Zhai, S.-L. Zhang, K.-J. Xia, H. Ding, X.-R. Song, W.-F. Tian, Y.-M. Liang and Q. Xiao, Photo-Induced Nickel-Mediated Cross-Electrophile Coupling for Alkylated Allenes via Electron Donor-Acceptor Complexes, Org. Chem. Front., 2023, 10, 298–303.
11. (a) B. Sun, P.-X. Li, Y. Jiang, L.-L. Yang, P.-Y. Huang, R.-P. Shen, M.-J. Chen, J.-Y. Wang and C. Jin, Visible-Light-Induced Desaturative β-Alkoxyoxalylation of N-Aryl Cyclic Amines with Difluoromethyl Bromides and H₂O Via a Triple Cleavage Process, Org. Lett., 2023, 25, 6773–6778; (b) B. Sun, Y. Wang, J. Wang, M. Chen, Z. Zhong, J. Wang and C. Jin, Photoredox-Catalyzed Redox-Neutral Decarboxylative C-H Acylations of Coumarins with α-Keto Acid, Org. Lett., 2023, 25, 2466–2470; (c) B. Sun, Y. Jiang, P.-Y. Huang, P.-X. Li, C. Lv, Y. Xu, J.-Y. Wang and C. Jin, Photoinduced Desaturative β-C(sp3)-H Amidation of N-Phenylpiperidine with Phthalimide Driven by Electron Donor-Acceptor Complexes, Org. Chem. Front., 2023, 10, 4758–4763; (d) Y. Xu, P. Huang, Y. Jiang, C. Lv, P. Li, J. Wang, B. Sun and C. Jin, Photo-Triggered Halodecarboxylation of Aliphatic Carboxylic Acids via Cerium-Mediated Ligand-Tometal Charge Transfer in Water, Green Chem., 2023, 25, 8741–8747; (e) P. Huang, Z. Yan, J. Ling, P. Li, J. Wang, J. Li, B. Sun and C. Jin, Catalyst-Free Intramolecular Radical Cyclization Cascades Initiated by the Direct Homolysis of Csp3-Br under Visible Light, Green Chem., 2023, 25, 3989–3994; (f) J. Wang, B. Shao, H. Ge, Y. Li, H. Qi and L. Xiao, Visible-Light-Induced Regioselective Radical Oxo-Amination of Alkenes with O₂ as the Oxygen Source, Org. Lett., 2023, 25, 5333–5338.
12. H.-A. S. Abbasa, R. Al-Marhabi, S. I. Eissa and Y. A. Ammar, Molecular Modeling Studies and Synthesis of Novel Quinoxaline Derivatives with Potential Anticancer Activity as Inhibitors of c-Met Kinase, Bioorg. Med. Chem., 2015, 23, 6560–6572.
13. A. I. Zbruyev, F. G. Yaremenko, V. A. Chebanov, S. M. Desenko, O. V. Shishkin, E. V. Lukinova and I. V. Knyazeva, Synthesis and Study of New 2-aryl-1-(4-Nitrophenyl)-1,1a-Dihydroazireno[1,2-a]quinoxaline Derivatives, Russ. Chem. Bull., 2006, 55, 362–368.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01309c

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