Cu-catalyzed oxidative coupling of alkylarenes with tertiary C(sp³)–H bonds via C–H activation

Abstract

An efficient Cu-catalyzed cross-dehydrogenative coupling (CDC) of oxindoles, fluorenes and xanthenes with alkylarenes containing primary and secondary benzylic C–H bonds was developed. The method is capable of forming highly hindered bonds (adjacent quaternary/ternary centers) and permits direct access to highly functionalized oxindoles, fluorenes and xanthenes with good functional group compatibility. This oxidative protocol is operationally simple and the synthetic utility was demonstrated by a gram-scale reaction while maintaining the yield. Further synthetic transformations of this product proceeded in high yield. Based on observations from a radical capture experiment, the transformation is proposed to proceed via a radical process.

---

Introduction

Cross-dehydrogenative coupling (CDC) is a particularly atom-economic and sustainable process to construct new C–C bonds.¹ Direct C–H functionalization provides an especially useful entry to more complex structures from commodity petroleum products including toluene and xylenes.² There has been growing interest in directly functionalizing benzylic C(sp³)–H bonds, which circumvents pre-functionalization steps and improves overall atom economy. In this regard, metal-based (Pd,^3,4 Fe,⁵ Co,⁶ Ni⁷) C–H activation strategies have been developed to directly functionalize benzylic C–H bonds. The discovery of the Kharasch–Sosnovsky reaction in 1958⁸ highlighted the potential of low-cost and abundant copper salts in C–H functionalization and there has been a resurgence in examining the reactivity of these systems. Examples include copper catalyzed couplings of benzylic C(sp³)–H with trimethylcyanide,⁹ N-pyrimidylindoles,¹⁰ arenes,¹¹ arylboronates,¹² amides,¹³ 1,3-dicarbonyls,¹⁴ and N-oxides.¹⁵ In addition, photo-catalytic C–H functionalization of toluene and its derivatives is emerging as a sustainable process.¹⁶ However, existing methods have intrinsic drawbacks such as requiring significant acidification of the benzylic position through electron-withdrawing groups or the coupling partner is restricted to C–X (X = O, N, S etc.) or C(sp²)–H bonds. To the best of our knowledge, the CDC of C(sp³)–H systems with C(sp³)–H bond of toluene derivatives remains limited.^3,17

Oxindoles with 3,3′disubstitution are found in an array of natural products and bioactive compounds.¹⁸ A number of synthetic methods have been developed to generate this structural type with much attention directed toward formation of the tetrasubstituted C3-center. The C3 nitration,¹⁹ hydroxylation,²⁰ arylation,²¹ chlorination,²² peroxidation,²³ alkynylation,²⁴ olefination²⁵ and sulfonation²⁶ of 3-substituted oxindoles have been reported. For example, redox neutral Pd-catalyzed allylation of oxindoles has been achieved using alkynes and enynes.²⁷ A corresponding oxidative method with a palladium NHC catalyst has been reported used allylbenzene as allylic alkyl donor (Scheme 1a).²⁸ However, reaction of oxindoles or fluorenes with toluene derivatives especially secondary benzylic derivatives cannot be achieved by these methods nor by simple alkylation with secondary halides. Recently, our group discovered a Pd catalyzed oxidative coupling of oxindoles with toluene.³ However, halogenated toluene and 3-alkyl substituted oxindoles were not applicable with this Pd catalytic system (Scheme 1b). Inspired by precedent from the Kharasch–Sosnovsky reaction and our previous work on oxidative coupling,²⁹ we disclose herein the discovery of a Cu catalyzed benzylic C(sp³)–H bond activation that accomplishes CDC with oxindoles, fluorenes, and xanthenes (Scheme 1c).

Scheme 1 Transition metal catalysed oxidative alkylation of 3-substituted oxindoles.

Results and discussion

Our studies commenced using 1-methyl-3-phenylindolin-2-one (1a) and toluene (2a) (Table 1). Treatment 1a with 10 mol% of CuI, 20 mol% of 1,10-phenanthroline (L1), and t-BuOOt-Bu in toluene (2a, 1.5 mL) at 100 °C for 24 h led to product 3aa in 52% yield (Table 1, entry 1). Subsequently, different copper salts, such as CuCl, CuBr·DMS, Cu(OTf)₂, Cu(OAc)₂, CuBr₂ and CuBr (entries 2–7), were examined. CuBr was found to afford 3aa in higher yield (62%). Examination of alternate oxidants (entries 8–13) did not lead to an improvement in yield. Assessment of different ligands (entries 14–18) revealed that the initial ligand L1 provided the best results. Higher temperatures (135 °C, entries 19 and 20) enhanced the product of 3aa (83%). Finally, controls showed that the yield of 3aa decreased significantly in the absence of copper catalyst or ligand (entries 21 and 22).

Table 1 Reaction development^a

Entry	Catalyst	Ligand	Oxidant	T (°C)	Yield (%)
a Reaction conditions: 1a (0.15 mmol) and 2a (0.1 M), at the indicated temperature for 24 h under argon. Yields determined by ^1H NMR spectroscopic analysis of the mixture relative to 4,4′-di-tert-butylbiphenyl as an internal standard.b CHP = cumene hydroperoxide, NFSI = N-fluorobenzenesulfonimide.c Isolated yields.
1	CuI	L1	t-BuOOt-Bu	100	52
2	CuCl	L1	t-BuOOt-Bu	100	51
3	CuBr·DMS	L1	t-BuOOt-Bu	100	27
4	Cu(OTf)2	L1	t-BuOOt-Bu	100	23
5	Cu(OAc)2	L1	t-BuOOt-Bu	100	31
6	CuBr2	L1	t-BuOOt-Bu	100	30
7	CuBr	L1	t-BuOOt-Bu	100	62
8	CuBr	L1	t-BuOOH	100	0
9	CuBr	L1	BzOOBz	100	36
10	CuBr	L1	CHP^b	100	0
11	CuBr	L1	NFSI^b	100	0
12	CuBr	L1	t-BuOOBz	100	56
13	CuBr	L1	K2S2O8	100	0
14	CuBr	L2	t-BuOOt-Bu	100	27
15	CuBr	L3	t-BuOOt-Bu	100	34
16	CuBr	L5	t-BuOOt-Bu	100	43
17	CuBr	L5	t-BuOOt-Bu	100	44
18	CuBr	L6	t-BuOOt-Bu	100	50^c
19	CuBr	L1	t-BuOOt-Bu	120	67^c
20	CuBr	L1	t-BuOOt-Bu	135	83^c
21	—	L1	t-BuOOt-Bu	135	6
22	CuBr	—	t-BuOOt-Bu	135	30

---

With the optimized conditions, the reactions of toluene with a series of oxindoles was examined (Table 2). When the C3-aryl contained electron-donating or electron-withdrawing substituents (3ba, 3ca, 3ea, 3fa, 3ha), good reactivity was observed. With oxindoles bearing an electron-donating (Me) or electron-withdrawing substituent (Cl) in the 5- and 6-positions, respectively, the corresponding products were achieved in high yields (3da, 3ga). The naphthyl group in the C3-position was also tolerated, affording 3ia in 55% yield. Replacement of the C3-aryl group with an alkyl group (3-methyl oxindole) led to successful benzylation with toluene (3ja), albeit in lower yield (30%). It should be noted that this substrate did not react with our previous Pd system.³ The N-benzyl oxindole congener was equally reactive as the N-methyl (3ka vs. 3aa). However, the N-Boc version was less reactive (3la, 22%) indicating that the acidity of the oxindole C–H bond was not the primary contributor to reactivity. Consistent with this trend, an electron-rich N-pyrrole substituent at the C3-position of the oxindole also gave rise to high yields with toluene (3ma, 3na, 3oa).

Table 2 Cu-catalyzed benzylation of oxindoles^a,b

a Reaction conditions: 1 (0.15 mmol), CuBr (10 mol%), phenanthroline (20 mmol%), t-BuOOt-Bu (4 equiv.) in tolyl analogs 2 (1.5 mL, 0.1 M), 135 °C, 24 h.b Isolated yield.

---

The scope of the benzylic hydrocarbons was next examined with 1a (Table 2). Various xylenes (p-, m-, o-) were effective giving high yields of the corresponding products (75–90%). Alkylarenes bearing an electron-donating methoxy or tert-butyl group afforded products 3ae and 3af in 55% and 79% yields, respectively. Even substrates such as mesitylene, halo-substituted toluene, which were not reactive in the previous Pd system,³ smoothly coupled with 1a to afford corresponding products in 36–69% yields (3ag–ai, 3ak, 3al), reflecting the high potential for further synthetic transformations. Further, 4-methybiphenyl and 2-methyl-naphthalene underwent reaction to give the target products 3aj and 3am in 57% and 35% yields, respectively. As for ethylbenzene, instead of the activation in the terminal CH₃ position,³ the benzylic position was activated in this protocol to afford oxindole 3an with adjacent quaternary and tertiary centers in 74% yield. The potential to generate highly hindered arrays is particularly notable.

Since efficient methods to prepare of highly substituted fluorenes are limited, we next examined whether fluorenyl substrates would be effective in these transformations.

Fluorenes are widely used in pharmaceuticals, dyes, organic light emitting diodes, polymer light emitting diodes, solar cells, fuel cells, etc.³⁰ With our previously reported Pd system,³ over 95% of fluorene 4a was unreacted when subjected toluene. However, fluorenes (4) underwent surprisingly robust reaction with a series of alkylbenzenes (2) under the present copper catalyzed conditions (Table 3). Little difference was observed between substrates with electron-neutral (5aa), electron-donating (5ba–5ea), and electron-withdrawing (5fa–5ja) groups regardless of their position. Notably, fluorene derivatives containing additional conjugation (4k) or heterocycle groups (4l–4n) also provided the corresponding products in good yields (5ka–5na). Moreover, this CDC system even worked well with a heterocyclic isoindoline analog (5oa).

Table 3 Cu-catalyzed benzylation of flourenes^a,b

a Reaction conditions: 4 (0.15 mmol), CuBr (10 mol%), phenanthroline (20 mmol%), t-BuOOt-Bu (4 equiv.) in tolyl analogs 2 (1.5 mL, 0.1 M), 135 °C, 24 h.b Isolated yield.c Run under 105 °C for 20 h.

---

Subsequently, a variety of benzylic hydrocarbons was investigated under the optimized conditions with fluorenes (Table 3, bottom). Methylarenes bearing both electron-donating and electron-withdrawing substituents were successfully incorporated in similar yields to afford the corresponding products (5ab–5ai). The results with the electron-withdrawing substituents (5ag–5ah) is notable as such systems fail with other protocols.³ Of particular note, mesitylene only gave the monobenzylation product in 91% yield (5aj). When the secondary benzylic versions of 2 were explored, products arising from coupling at the benzylic position were obtained in 65–82% yields (5ak–5am), which is quite different from our developed Pd system.³ With p-ethyltoluene, inseparable regioisomers (5an, 5an′) were obtained in 81% overall yield. The predominance of reaction at the more hindered secondary vs. the primary position in this substrate foreshadows a radical mechanism where the bond strength of the substrate determines the relative reactivity. Remarkably, methylheteroarenes including 2-methylfuran, 2-methylthiophene also performed well under the optimized conditions, providing the desired products in 54% and 62% yields, respectively (5ao, 5gq). Another highlight is the efficiency of the Cu catalytic system in allylic C–H activation, delivering 5ap from allylbenzene in 81% yield without observation of any branched product which likely reflects formation of the least hindered allyl copper intermediate.

Remarkably, the benzylation process also allows 9-aryl xanthenes to serve as the cross-coupling partner; this moiety is a common skeleton in perovskite solar cells and dyes.³¹ By decreasing the temperature to 120 °C with toluene, product 7aa was obtained in 53% yield (Table 4). Three different xanthenes afforded the products in good to excellent yields (6a, 6b, 6c, 40–97%). A particularly broad range of benzylic hydrocarbons were highly effective including para-tert-butyltoluene (7ab, 40%), mesitylene (7ac, 56%), and meta-bromotoluene (7bd, 65%); the presence of bromo substituent in the latter was compatible with the reaction conditions and allows for additional future functionalization. Reactions at secondary benzylic centers were even more effective: ethylbenzene (7be, 79%; 7ce, 73%), propylbenzene (7bf, 97%; 7cf, 84%), butylbenzene (7bg, 56%; 7cg, 71%). And 7cg was obtained in 65% yield in a 2 mmol scale. The formation of these hindered bonds generating contiguous quaternary and tertiary centers is expected to lead to novel conformationally defined materials. This hypothesis is supported by the X-ray crystallographic structure of 7cg (Table 4) which shows an antiperiplanar arrangement of the xanthyl and n-propyl groups. This conformation persists in solution as determined from ¹H NMR coupling constants (see SI). Unfortunately, 1-methylindolin-2-one was not compatible under our catalytic conditions and benzylic hydrocarbons bearing electron withdrawing groups (–COOMe, –CN) failed to deliver any detectable products indicating that the current catalytic system is sensitive to the electronic and structural features of the coupling partner. When other potential coupling partners such as tetrahydrofuran, dioxane, cyclohexane were attempted with oxindole under optimized conditions, they did not give desired products. Further details regarding unsuccessful substrates are provided in the SI. Despite these limitations, this work represents a crucial contribution for copper-catalyzed oxidative coupling of alkylarenes with tertiary C(sp³)–H Bonds, and is complementary to our previously developed Pd catalytic system.³

Table 4 Cu-catalyzed benzylation of xanthenes^a,b

a Reaction conditions: 6 (0.15 mmol), CuBr (10 mol%), phenanthroline (20 mmol%), t-BuOOt-Bu (4 equiv.) in tolyl analogs 2 (1.5 mL, 0.1 M), 120 °C, 24 h.b Isolated yield.

---

The practicality of this methodology was further demonstrated by a gram scale up. A 1.1 g scale reaction of 4c under standard conditions afforded desired product 5ca in 62% yield (Scheme 2a). Treatment of the obtained product 5ca (800 mg) with BBr₃ smoothly effected demethylation to furnish fluorene 8 in 99% yield, providing a useful building block for further fluorene functionalization with reactive phenolic hydroxyl group.

Scheme 2 Scale up reaciton and synthetic transformation.

To gain insight into the mechanism, additional experiments were undertaken (Scheme 3). Radical scavengers such as TEMPO or BHT (2,4-di-tert-butyl-4-methylphenol) completely inhibit the reaction with both the oxindole and fluorene substrates (Scheme 3a and b). GC-MS analysis of the reaction mixture after 15 h revealed the formation of two byproducts 1,2-diphenylethane and (tert-butoxymethyl)benzene (Scheme 3c). No radical initiated adduct was observed when reaction was conducted in dioxane instead of toluene (Scheme 3d).³² These results imply that any stabilized oxindole/fluorene/xanthene radicals formed are sequestered by copper from which C–C reductive elimination is more favorable than C–O reductive elimination.

Scheme 3 Mechanistic experiments.

Intermolecular competing kinetic isotope effect (KIE) experiments were carried out and significant kinetic isotopic effects were observed (k_H/k_D = 6.7 for oxindole 1a, and k_H/k_D = 5.6 for fluorene 4a) (Scheme 3e and f). A somewhat lower KIE value (1.6) was observed in a parallel KIE experiment for the benzylation of 1a (see SI for details). The results from these experiments suggest that C(sp³)–H bond cleavage to form the benzylic radical is only partly rate-limiting and that another mechanistic step may also contribute to the catalytic turnover rate (e.g., generation of the reactive radical via activation of DTBP by Cu^I or solvent cage effects that partially mask the intrinsic isotope effect in the parallel experiment).^9,33 The high reactivity of the tert-butoxy radical is expected to lead to no KIE, but complexation to species present or formation of less reactive radicals (i.e. those from 1/4/6 or bromine atom) that subsequently react with toluene would give rise to a modest parallel KIE of the magnitude seen here.³⁴

From these control experiments and previous reports,^12,35 a plausible mechanism for this Cu catalyzed CDC with benzylic C(sp³)–H is proposed in Scheme 4, with the reaction of oxindole (1a) and toluene (3a) shown as an example. At the temperatures utilized, homolysis of t-BuOOt-Bu is expected to provide tert-butoxyl radicals. This species would likely first react with the (phen)CuIBr to form a (phen)CuIIBr(Ot-Bu) adduct.³⁶ Of the organic species, the oxindoles/fluorenes/xanthenes have the weaker bonds (≤72 kcal mol⁻¹) 3b and would likely undergo radical abstraction first as tert-butoxyl radicals form. The higher yields observed with more electron rich substrates (e.g. 3aa and 3ka vs. 3la) is consistent with formation of this radical species. The resultant stabilized radicals could combine with the Cu^II adduct which may be accompanied by bromine atom release.^37,38 Either this bromine atom or an additional tert-butoxyl radical could then abstract the stronger C–H bond of the alkyl arene to generate a Cu^III intermediate.³⁵ Steric hindrance would disfavor coordination of two equivalents of the oxindole/fluorene/xanthene to the copper center. If two of the oxindole/fluorene/xanthene radicals did combine, they would give rise to a dimer that would serve as a source of the respective radicals.³ Recombination of two benzylic radicals via the copper center (or in solution) is expected to be less likely as the concentration of this species will be lower due to the stronger bond dissociation energy of the benzylic C–H bonds (90 kcal mol⁻¹ for toluene, 78 kcal mol⁻¹ for ethylbenzene),³⁹ but was observed to some extent (Scheme 3c). Reductive elimination from the Cu^III intermediate³⁵is expected to be rapid giving rise to the observed adducts such as 3aa.

Scheme 4 Proposed mechanism.

Conclusions

In conclusion, a copper-catalyzed cross-dehydrogenative coupling of oxindoles/fluorenes/xanthenes with benzylic hydrocarbons has been discovered. This discovery adds a new dimension to oxidative copper reaction by permitting the union of two sp³ C–H centers to form highly hindered bonds. Additional highlights include straightforward construction of quaternary centers by addition of primary and secondary benzylic hydrocarbons. Considering the importance of the fluorene, oxindole and xanthene frameworks in medicinal, synthetic organic chemistry, and material science, this transformation is expected to find further applications.

Author contributions

G. H. and M. C. K. conceived of the project. G. H. and P. D. N. designed the experiments. G. H., P. D. N., and W. G. P. performed the research. G. H., P. D. N., and M. C. K. wrote the manuscript. M. C. K. Supervised the project and reviewed the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information (SI): all experimental data, procedures for data analysis, and pertinent data sets. See DOI: https://doi.org/10.1039/d6ob00723f.

CCDC 1939223 contains the supplementary crystallographic data for this paper.⁴⁰

Acknowledgements

We are grateful to the NSF (2400215) and the NIH (GM131902) for financial support of this research. Partial instrumentation support was provided by the NIH and NSF (1S10RR023444, 1S10RR022442, 3R01GM118510-03S, 3R01GM087605-06S1, CHE-0840438, CHE-0848460, 1S10OD011980, CHE-1827457) as well as the Vagelos Institute for Energy Science and Technology. Dr Patrick Carroll (UPenn) and Dr Michael R. Gau are acknowledged for obtaining the X-ray structure and X-ray crystallography analysis.

References

1. (a) G. Song, F. Wang and X. Li, C–C, C–O and C–N Bond Formation via Rhodium(III)-Catalyzed Oxidative C–H Activation, Chem. Soc. Rev., 2012, 41, 3651–3678; (b) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Recent Advances in the Transition Metal-Catalyzed Twofold Oxidative C–H Bond Activation Strategy for C–C and C–N Bond Formation, Chem. Soc. Rev., 2011, 40, 5068–5083; (c) C. S. Yeung and V. M. Dong, Catalytic Dehydrogenative Cross-Coupling: Forming Carbon− Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds, Chem. Rev., 2011, 111, 1215–1292; (d) B. V. Varun, J. Dhineshkumar, K. R. Bettadapur, Y. Siddaraju, K. Alagiri and K. R. Prabhu, Recent Advancements in Dehydrogenative Cross Coupling Reactions for CC Bond Formation, Tetrahedron Lett., 2017, 58, 803–824; (e) G. Deng, L. Zhao and C. Li, Ruthenium-catalyzed Oxidative Cross-Coupling of Chelating Arenes And Cycloalkanes, Angew. Chem., Int. Ed., 2008, 47, 6278–6282; (f) B. Liegault and K. Fagnou, Palladium-catalyzed Intramolecular Coupling of Arenes and Unactivated Alkanes In Air, Organometallics, 2008, 27(19), 4841–4843; (g) S. Guin, S. K. Rout, A. Banerjee, S. Nandi and B. K. Patel, Four tandem C–H activations: a Sequential C–C and C–O Bond Making via a Pd-Catalyzed Cross Dehydrogenative Coupling (CDC) Approach, Org. Lett., 2012, 14, 5294–5297; (h) D. P. Patel, V. K. Patel and S. K. Singh, Visible Light-Induced Cross-Dehydrogenative Coupling of N-Heterocyclic Compounds: Green and Efficient Synthetic Strategies, Org. Chem. Front., 2026, 13, 597–655.
2. (a) M. A. Fahim, A. T. Al-Sahhaf and A. Elkilani, Fundamentals of Petroleum Refining, Elsevier Science, 2010; (b) M. Shigeno, A. Kajima, E. Toyama, T. Korenaga, H. Yamakoshi, K. N. Kumada and Y. Konda, LiHMDS-Mediated Deprotonative Coupling of Toluenes with Ketones, Chem. – Eur. J., 2023, 29, e202203549.
3. (a) G. Hong, P. D. Nahide, U. K. Neelam, P. Amadeo, A. Vijeta, J. M. Curto, C. E. Hendrick, K. F. VanGelder and M. C. Kozlowski, Palladium-Catalyzed Chemoselective Activation of sp³ vs. sp² C–H Bonds: Oxidative Coupling to Form Quaternary Centers, ACS Catal., 2019, 9, 3716–3724; (b) J. M. Curto and M. C. Kozlowski, Chemoselective Activation of sp³ vs. sp² C–H Bonds with Pd(II), J. Am. Chem. Soc., 2015, 137, 18–21.
4. (a) S.-C. Sha, S. Tcyrulnikov, M. Li, B. Hu, Y. Fu, M. C. Kozlowski and P. J. Walsh, Cation–π Interactions in the Benzylic Arylation of Toluenes with Bimetallic Catalysts, J. Am. Chem. Soc., 2018, 140, 12415–12423; (b) P. Xie, Y. J. Xie, B. Qian, H. Zhou, C. Xia and H. M. Huang, Palladium-Catalyzed Oxidative Carbonylation of Benzylic C–H Bonds via Nondirected C(sp³)–H Activation, J. Am. Chem. Soc., 2012, 134, 9902–9905; (c) P. Xie, C. Xia and H. Huang, Palladium-catalyzed Oxidative Aminocarbonylation: A New Entry to Amides via C–H Activation, Org. Lett., 2013, 15, 3370–3373; (d) H. Liu, G. Shi, S. Pan, Y. Jiang and Y. Zhang, Palladium-Catalyzed Benzylation of Carboxylic Acids with Toluene via Benzylic C–H Activation, Org. Lett., 2013, 15, 4098–4101.
5. (a) T. Tanaka, K. Hashiguchi, T. Tanaka, R. Yazaki and T. Ohshima, Chemoselective Catalytic Dehydrogenative Cross-Coupling of 2-Acylimidazoles: Mechanistic Investigations and Synthetic Scope, ACS Catal., 2018, 8, 8430–8440; (b) Z. Li, L. Cao and C.-J. Li, FeCl₂-Catalyzed Selective C-C Bond Formation by Oxidative Activation of a Benzylic C-H Bond, Angew. Chem., Int. Ed., 2007, 46, 6505–6507; (c) H.-R. Wu, H.-Y. Huang, C.-L. Ren, L. Liu, D. Wang and C.-J. Li, FeIII-Catalyzed Cross-Dehydrogenative Arylation (CDA) between Oxindoles and Arenes under an Air Atmosphere, Chem. – Eur. J., 2015, 21, 16744–16748.
6. Y. F. Guo, B. H. Xu, T. Li, L. Wang and S. J. Zhang, Cobalt(II)-Catalyzed Oxidative Esterification of Aldehydes: A Cooperative Effect Between Cobalt And Iodide Ions, Org. Chem. Front., 2016, 3, 47–52.
7. Y. Aihara, M. Tobisu, Y. Fukumoto and N. Chatani, Ni(II)-Catalyzed Oxidative Coupling between C(sp²)–H in Benzamides and C(sp³)–H in Toluene Derivatives, J. Am. Chem. Soc., 2014, 136, 15509–15512.
8. (a) M. S. Kharasch and G. Sosnovsky, The Reactions of t-Butyl Perbenzoate and Olefins—A Stereospecific Reaction, J. Am. Chem. Soc., 1958, 80, 756; (b) M. S. Kharasch and A. Fono, Communications-Radical Substitution Reactions, J. Org. Chem., 1958, 23, 325–326.
9. W. L. Zhang, F. Wang, S. D. McCann, D. Wang, P. Chen, S. S. Stahl and G. Liu, Enantioselective Cyanation of Benzylic C–H Bonds via Copper-Catalyzed Radical Relay, Science, 2016, 353, 1014–1018.
10. H. J. Zhang, F. Su and T. B. Wen, Copper-Catalyzed Direct C2-Benzylation of Indoles with Alkylarenes, J. Org. Chem., 2015, 80, 11322–11329.
11. (a) T. E. Storr, C. J. Teskey and M. F. Greaney, Cross-Dehydrogenative-Coupling of Alkoxybenzenes with Toluenes: Copper(II) Halide Mediated Tandem Halo/Benzylation of Arenes, Chem. – Eur. J., 2016, 22, 18169–18178; (b) F. Lv, E. Hao, C. Yu, H. Wang, L. Jiao and N. Boens, Copper-catalyzed α-Benzylation of Bodipys via Radical-Triggered Oxidative Cross-Coupling of Two C–H Bonds, Chem. Commun., 2018, 54, 9059–9062.
12. (a) A. Vasilopoulos, S. L. Zultanski and S. S. Stahl, Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of Inexpensive Alkylarenes Enabling Direct Access to Diarylalkanes, J. Am. Chem. Soc., 2017, 139, 7705–7708; (b) W. Zhang, P. Chen and G. Liu, Copper-Catalyzed Arylation of Benzylic C–H Bonds with Alkylarenes As The Limiting Reagents, J. Am. Chem. Soc., 2017, 139, 7709–7712.
13. H.-T. Zeng and J.-M. Huang, Copper-Catalyzed Ligand-Free Amidation of Benzylic Hydrocarbons And Inactive Aliphatic Alkanes, Org. Lett., 2015, 17, 4276–4279.
14. N. Borduas and D. A. Powell, Copper-Catalyzed Oxidative Coupling of Benzylic CH Bonds With 1, 3-Dicarbonyl Compounds, J. Org. Chem., 2008, 73, 7822–7825.
15. L. Fan, Z. Zhang, T. Wang, Q. Liang and J. Zhao, Copper-Catalyzed Oxidative Functionalization of Benzylic C–H Bonds with Quinazoline 3-Oxides, Org. Chem. Front., 2018, 5, 2492–2495.
16. (a) F. Li, D. Tian, Y. Fan, R. Lee, G. Lu, Y. Yin, B Qiao, X. Zhao, Z. Xiao and Z. Jiang, Chiral Acid-Catalysed Enantioselective C− H Functionalization of Toluene And Its Derivatives Driven By Visible Light, Nat. Commun., 2019, 10, 1774–1783; (b) H. Liu, L. Ma, R. Zhou, X. Chen, W. Fang and J. Wu, One-pot Photomediated Giese Reaction/Friedel–Crafts Hydroxyalkylation/Oxidative Aromatization to Access Naphthalene Derivatives From Toluenes And Enones, ACS Catal., 2018, 8, 6224–6229; (c) R. Zhou, H. W. Liu, H. R. Tao, X. J. Yu and J. Wu, Metal-Free Direct Alkylation of Unfunctionalized Allylic/Benzylic Sp³ C–H Bonds Via Photoredox Induced Radical Cation Deprotonation, Chem. Sci., 2017, 8, 4654–4659; (d) D. Mazzarella, G. E. M. Crisenza and P. Melchiorre, Asymmetric Photocatalytic C–H Functionalization of Toluene and Derivatives, J. Am. Chem. Soc., 2018, 140, 8439–8443; (e) T. Kawasaki, N. Ishida and M. Murakami, Dehydrogenative Coupling of Benzylic and Aldehydic C–H Bonds, J. Am. Chem. Soc., 2020, 142, 3366–3370; (f) Y. Guo, J. Qi, H. Guo, R. Liu and R. Zhou, Cross-Coupling of Benzylic and Aldehydic C–H Bonds via Photocatalytic Tandem Radical–Radical Coupling and Acceptorless Alcohol Dehydrogenation, J. Org. Chem., 2024, 89, 2032–2038; (g) W. Yang, Z. Zhao, Y. Lan, Z. Dong, R. Chang, Y. Bai, S. Liu, S.-J. Li and L. Niu, Heterocoupling Two Similar Benzyl Radicals by Dual Photoredox/Cobalt Catalysis, Angew. Chem., Int. Ed., 2025, 64, e202421256.
17. (a) H. Yu, Y. Xu, R. Dong and Y. Fang, Direct Oxidative Cross-Coupling of Toluene Derivatives and N-Acyl-2-aminoacetophenones, Adv. Synth. Catal., 2017, 359, 39–43; (b) P. Kumar, T. Guntreddi, R. Singh and K. N. Singh, A Practical Protocol for the Synthesis of Bibenzyls via C (Sp³)–H Activation of Methyl Arenes Under Metal-Free Conditions, Org. Chem. Front., 2017, 4, 147–150; (c) R. Yazaki and T. Ohshima, Recent Strategic Advances for The Activation of Benzylic C–H Bonds For The Formation of C–C Bonds, Tetrahedron Lett., 2019, 60, 151225; (d) Z. Tong, X. Peng, Z. Tang, W.-J. Yang, W. Deng, S.-F. Yin, N. Kambe and R. Qiu, DTBP-Mediated Cross-Dehydrogenative Coupling of 3-Aryl Benzofuran-2 (3 H)-Ones With Toluenes/Phenols For All-Carbon Quaternary Centers, RSC Adv., 2022, 12, 35215–35220.
18. (a) R. Dalpozzo, G. Bartoli and G. Bencivenni, Recent Advances in Organocatalytic Methods for The Synthesis of Disubstituted 2-And 3-Indolinones, Chem. Soc. Rev., 2012, 41, 7247–7290; (b) J. J. Badillo, N. V. Hanhan and A. K. Franz, Enantioselective Synthesis of Substituted Oxindoles And Spirooxindoles with Applications In Drug Discovery, Curr. Opin. Drug Discovery Dev., 2010, 13, 758–776.
19. W. T. Wei, W. M. Zhu, W. W. Ying, Y. N. Wang, W. H. Bao, L. H. Gao, Y. J. Luo and H. Liang, Metal-Free Nitration of the C(sp3)−H Bonds of 2-Oxindoles through Radical Coupling Reaction at Room Temperature, Adv. Synth. Catal., 2017, 359, 3551–3554.
20. W. T. Wei, W. M. Zhu, Q. Shao, W. H. Bao, W. T. Chen, G. P. Chen, Y. J. Luo and H. Liang, Transition-Metal-Free C(sp3)–H Hydroxylation of 2-Oxindoles with Peroxides via Radical Cross-Coupling Reaction in Water, ACS Sustainable Chem. Eng., 2018, 6, 8029–8033.
21. H. R. Wu, H. Y. Huang, C. L. Ren, L. Liu, D. Wang and C. J. Li, FeIII-Catalyzed Cross-Dehydrogenative Arylation (CDA) between Oxindoles and Arenes under an Air Atmosphere, Chem. – Eur. J., 2015, 21, 16744–16748.
22. M. X. Zhao, Z. W. Zhang, M. X. Chen, W. H. Tang and M. Shi, Cinchona Alkaloid Catalyzed Enantioselective Chlorination of 3-Aryloxindoles, Eur. J. Org. Chem., 2011, 3001–3008.
23. D. L. Kong, L. Cheng, T. Yue, H. R. Wu, W. C. Feng, D. Wang and L. Liu, Cobalt-Catalyzed Peroxidation of 2-Oxindoles With Hydroperoxides, J. Org. Chem., 2016, 81, 5337–5344.
24. H. Y. Huang, L. Cheng, J. J. Liu, D. Wang, L. Liu and C. J. Li, Transition-Metal-Free Alkynylation of 2-Oxindoles through Radical–Radical Coupling, J. Org. Chem., 2017, 82, 2656–2663.
25. H. Y. Huang, H. R. Wu, F. Wei, D. Wang and L. Liu, Iodine-Catalyzed Direct Olefination Of 2-Oxindoles and Alkenes Via Cross-Dehydrogenative Coupling (CDC) In Air, Org. Lett., 2015, 17, 3702–3705.
26. C. D. Prasad, M. Sattar and S. Kumar, Transition-Metal-Free Selective Oxidative C(sp3)–S/Se Coupling of Oxindoles, Tetralone, and Arylacetamides: Synthesis of Unsymmetrical Organochalcogenides, Org. Lett., 2017, 19, 774–777.
27. (a) S. Gao, H. Liu, Z. Wu, H. Yao and A. Lin, Palladium-Catalyzed Allylic Alkylation with Internal Alkynes to Construct C–C And C–N Bonds In Water, Green Chem., 2017, 19, 1861–1865; (b) S. Gao, H. Liu, C. Yang, Z. Fu, H. Yao and A. Lin, Accessing 1, 3-Dienes via Palladium-Catalyzed Allylic Alkylation of Pronucleophiles With Skipped Enynes, Org. Lett., 2017, 19, 4710–4713.
28. R.-B. Hu, C.-H. Wang, W. Ren, Z. Liu and S.-D. Yang, Direct Allylic C–H Bond Activation to Synthesize [Pd(η3-cin)(IPr)Cl] Complex: Application in the Allylation of Oxindoles, ACS Catal., 2017, 7, 7400–7404.
29. (a) H. Kang, A. L. Jemison, E. Nigro and M. C. Kozlowski, Oxidative Coupling of 3-Oxindoles with Indoles and Arenes, ChemSusChem, 2019, 12, 3144–3151; (b) G. Hong, P. D. Nahide and M. C. Kozlowski, Cyanomethylation of Substituted Fluorenes and Oxindoles with Alkyl Nitriles, Org. Lett., 2020, 22, 1563–1568; (c) P. Amadeo, B. Bhaskararao, Y.-F. Yang and M. C. Kozlowski, Inherent Selectivity of Pd C–H Activation From Different Metal Oxidation States, Organometallics, 2021, 40, 2290–2294; (d) P. Basnet, M. B. Sebold, C. E. Hendrick and M. C. Kozlowski, Copper Catalyzed Oxidative Arylation of Tertiary Carbon Centers, Org. Lett., 2020, 22, 9524–9528.
30. (a) L. Wang, G. W. Zhang, C. J. Ou, L. H. Xie, J. Y. Lin, Y. Y. Liu and W. Huang, Friedel–Crafts Bottom-Up Synthesis of Fluorene-Based Soluble Luminescent Organic Nanogrids, Org. Lett., 2014, 16, 1748–1751; (b) I. Osken, A. S. Gundogan, E. Tekin, M. S. Eroglu and T. Ozturk, Fluorene–Dithienothiophene-S,S-dioxide Copolymers. Fine-Tuning for OLED Applications, Macromolecules, 2013, 46, 9202–9210; (c) C. D. Andrade, C. O. Yanez, L. Rodriguez and K. D. Belfield, A Series of Fluorene-Based Two-Photon Absorbing Molecules: Synthesis, Linear and Nonlinear Characterization, And Bioimaging, J. Org. Chem., 2010, 75, 3975–3982; (d) H. Qi, C. Zhang, Z. Huang, L. Wang, W. Wang and A. J. Bard, Electrochemistry and Electrogenerated Chemiluminescence of 1, 3, 5-Tri (Anthracen-10-Yl)-Benzene-Centered Starburst Oligofluorenes, J. Am. Chem. Soc., 2016, 138, 1947–1954; (e) K. Miyatake, B. Bae and M. Watanabe, Fluorene-Containing Cardo Polymers as Ion Conductive Membranes for Fuel Cells, Polym. Chem., 2011, 2, 1919–1929.
31. (a) B. Xu, J. Zhang, Y. Hua, P. Liu, L. Wang, C. Ruan, Y. Li, G. Boschloo, E. M. J. Johansson, L. Kloo, A. Hagfeldt, A. K. Y. Jen and L. Sun, Tailor-Making Low-Cost Spiro [Fluorene-9, 9′-Xanthene]-Based 3D Oligomers for Perovskite Solar Cells, Chem, 2017, 2, 676–687; (b) M. Matsui, T. Yamamoto, K. Katitani, S. Biradar, Y. Kubota and K. Funabiki, UV–vis Absorption and Fluorescence Spectra, Solvatochromism, And Application to Ph Sensors Of Novel Xanthene Dyes Having Thienyl And Thieno[3,2-B]Thienyl Rings As Auxochrome, Dyes Pigm., 2017, 139, 533–540.
32. H. F. T. Klaire, A. F. G. Goldberg, D. C. Duquette and B. M. Stolz, Oxidative Fragmentations and Skeletal Rearrangements of Oxindole Derivatives, Org. Lett., 2017, 19, 988–991.
33. E. M. Simmons and J. F. Hartwig, On the Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by Transition-Metal Complexes, Angew. Chem., Int. Ed., 2012, 51, 3066–3072.
34. F. Gozzo, Radical and Non-Radical Chemistry of the Fenton-Like Systems in The Presence of Organic Substrates, J. Mol. Catal. A: Chem., 2001, 171, 1–22.
35. (a) H. Yu, Z. Li and C. Bolm, Nondirected Copper-Catalyzed Sulfoxidations of Benzylic C–H Bonds, Org. Lett., 2018, 20, 2076–2079; (b) C. Chen, X. H. Xu, B. Yang and F. L. Qing, Copper-Catalyzed Direct Trifluoromethylthiolation of Benzylic C–H Bonds via Nondirected Oxidative C(sp3)–H Activation, Org. Lett., 2014, 16, 3372–3375.
36. R. T. Gephart, C. L. McMullin, N. G. Sapiezynski, E. S. Jang, M. J. B. Aguila, R. Thomas, T. R. Cundari and T. H. Warren, Reaction of CuI with Dialkyl Peroxides: CuII-Alkoxides, Alkoxy Radicals, and Catalytic C–H Etherification, J. Am. Chem. Soc., 2012, 134, 17350–17353.
37. An alternate pathway would involve ligand exchange between the L₂CuII(Ot-Bu)Br and the oxindole/fluorene/xanthene to generate L₂CuIIIR(Ot-Bu)Br. This pathway is supported by the facile deprotonation of fluorene with tert-butoxide (2 h at rt in toluene). Subsequent reaction with a benzylic radical and loss of a bromine atom would yield L₂CuIIIR(Ot-Bu)Bn.
38. For an example of a fluorene Cu(II) complex; A. J. Edwards, M. A. Paver, P. R. Raithby, M.-A. Rennie, C. A. Russell and D. S. Wright, Preparation of Copper Organometallics via Nucleophilic substitution of CpCuPPh₃: Syntheses and X-Ray Structure Determinations of [Li(THF)₄]⁺ [(Fluorenyl)₂CuPPh₃] And [Cy₃PCu(^-C=Ctbu)₂Cu(PPh₃)₂], Organometallics, 1994, 13, 4967–4972.
39. S. J. Blanksby and G. B. Ellison, Bond Dissociation Energies of Organic Molecules, Acc. Chem. Res., 2003, 36, 255–263.
40. CCDC 1939223: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc232xlq.

---

Footnote

† These authors contributed equally to this work.

---