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. 2026 Sep 18. Online ahead of print. doi: 10.1039/d6sc06229f

Fluoride-activated silicon catalysis enables C(sp3)–H amination of cyclic benzylic ethers and amines using chloramine-T

Geun Ho Kim a,†, Huimyoung Byeon a,†, Dong Wan Kim a,†, Dae Won Kim a, Jung Woon Yang a,b,✉
PMCID: PMC13613150  PMID: 42798898

Abstract

Fluoride-activated silicon catalysis enables radical benzylic C(sp3)–H amination of cyclic benzylic ethers and amines with bench-stable chloramine-T under transition-metal-free conditions. Mechanistic studies support a previously unexplored fluoride-promoted silicon catalytic cycle involving N-silyl sulfonamide intermediates, radical-mediated hydrogen-atom transfer, oxocarbenium ion formation for N,O-aminals, and iminium ion formation for N,N-aminals, providing an efficient platform for direct benzylic C–N bond formation.

Fluoride-activated silicon catalysis enables transition-metal-free radical benzylic C(sp3)–H amination of cyclic benzylic ethers and amines using bench-stable chloramine-T as the nitrogen source.graphic file with name d6sc06229f-ga.webp

Introduction

Carbon–nitrogen (C–N) bond formation is one of the most fundamental transformations in organic synthesis because nitrogen-containing compounds are widely found in natural products, pharmaceuticals, and biologically active molecules.1–13 Consequently, substantial efforts have been devoted to developing efficient methods for C–N bond construction.14–22 Aminals represent an important class of nitrogen-containing compounds owing to their widespread occurrence in bioactive molecules and their utility as versatile synthetic intermediates.23–27 Among aminals, hemiaminal ethers (N,O-aminals) and N,N-aminals have attracted considerable attention because both motifs are prevalent in biologically relevant compounds and serve as versatile building blocks in organic synthesis.28 Accordingly, direct C(sp3)–H amination has emerged as an efficient strategy for their preparation by enabling rapid C–N bond formation from readily available benzylic substrates.29–32

For cyclic benzylic ethers, direct C(sp3)–H amination has been accomplished through transition-metal-catalyzed nitrene insertion using N-sulfonylimino-λ3-iodanes or chloramine-T, hypervalent bromane-mediated metal-free amination, and oxidative cross-dehydrogenative coupling (CDC) reactions with nitrogen nucleophiles (Scheme 1a(i–iii)).29,33–42 In parallel, direct α-C(sp3)–H amination of cyclic benzylic amines has relied on iodine- or halogen-mediated oxidation and radical-mediated hydrogen-atom transfer (HAT) or single-electron transfer (SET) processes employing N-halo nitrogen sources to furnish N,N-aminals (Scheme 1a(iv and v)).43–53 Although these methods efficiently provide access to aminal derivatives, the syntheses of N,O-aminals and N,N-aminals have progressed independently, relying on fundamentally different activation modes, catalytic systems, and nitrogen-transfer reagents.33–53

Scheme 1. Representative strategies for direct α-C(sp3)–H amination of cyclic benzylic ethers and amines.

Scheme 1

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Most existing methods require transition-metal catalysts, hypervalent halogen reagents, halogen mediators, or stoichiometric oxidants, increasing operational complexity and waste generation.54,55 Consequently, unified transition-metal-free catalytic platforms capable of directly converting both cyclic benzylic ethers and cyclic benzylic amines into the corresponding N,O- and N,N-aminals using a common nitrogen source remain scarce.

Herein, we report a silicon-catalyzed direct C(sp3)–H amination of cyclic benzylic ethers and cyclic benzylic amines using readily available chloramine-T as the nitrogen source (Scheme 1b). This transition-metal-free protocol provides efficient access to both N,O-aminals and N,N-aminals under mild reaction conditions with broad functional-group compatibility. By employing a single silicon catalyst and a common nitrogen-transfer reagent across two complementary substrate classes, this work establishes a unified catalytic strategy for benzylic C(sp3)–H amination and the synthesis of structurally distinct aminals.

Results and discussion

To identify the factors governing the silicon-catalyzed α-C(sp3)–H amination of cyclic benzylic ethers, the reaction of isochroman 1a with chloramine-T trihydrate 3 was systematically evaluated by varying the catalyst, additive, solvent, and temperature (Table 1). Given the dual requirements for chloramine-T activation and selective benzylic C–N bond formation, the reaction proved highly sensitive to both the catalyst and the reaction medium. In the absence of both catalyst and additive, N,O-aminal 4a was obtained in only 24% yield at room temperature, and increasing the reaction temperature to 60 °C improved the yield to 46% (entries 1 and 2). These results indicate that chloramine-T alone is capable of promoting the transformation, albeit with limited efficiency. The influence of the chlorosilane catalyst was next examined using a series of structurally distinct silyl chlorides. TMSCl (I), TBDPSCl (II), TBDMSCl (III), and TIPSCl (IV) afforded 4a in 44, 69, 75, and 84% yields, respectively (entries 3–6), with TIPSCl (IV) providing the highest yield. Solvent screening identified CH3CN as the optimal medium, whereas CH3NO2 completely suppressed the reaction and CHCl3, benzene, and DMF afforded only low to moderate yields (entries 7–10). Evaluation of additives revealed a pronounced fluoride effect. K2CO3 completely inhibited the reaction, while 4 Å molecular sieves, NaF, CsF and TMAF failed to improve the reaction relative to TIPSCl alone, affording 4a in 61–80% yields (entries 12–15 versus entry 6). In contrast, KF increased the yield to 99% (entry 16), establishing the TIPSCl/KF combination as the optimal catalytic system for the α-C(sp3)–H amination of cyclic benzylic ethers.

Table 1. Optimization of reaction conditionsa.

graphic file with name d6sc06229f-u1.jpg
Entry Catalyst Additive Solvent T (°C) T (°C)
1 None None CH3CN rt 24
2 None None CH3CN 60 46
3 TMSCl (I) None CH3CN rt 44
4 TBDPSCl (II) None CH3CN rt 69
5 TBDMSCl (III) None CH3CN rt 75
6 TIPSCl (IV) None CH3CN rt 84
7 TIPSCl (IV) None CH3NO2 rt n.d.
8 TIPSCl (IV) None CHCl3 rt 4
9 TIPSCl (IV) None Benzene rt 6
10 TIPSCl (IV) None DMF rt 25
11 TIPSCl (IV) K2CO3 CH3CN rt n.d.
12 TIPSCl (IV) MS 4 Å CH3CN rt 78
13 TIPSCl (IV) NaF CH3CN rt 80
14 TIPSCl (IV) CsF CH3CN rt 61
15 TIPSCl (IV) TMAF CH3CN rt 80
16 TIPSCl (IV) KF CH3CN rt 99
17b TMSCl (I) KF CH3CN rt 51
18b TBDPSCl (II) KF CH3CN rt 43
19b TBDMSCl (III) KF CH3CN rt 54
20b TIPSCl (IV) KF CH3CN rt 67
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a

Reaction conditions: 1a or 2a (0.5 mmol), 3 (1.2 equiv.), KF (2 equiv.), TIPSCl (IV, 20 mol%), CH3CN (0.2 M, 2.5 mL), at the corresponding temperature, time, under Ar atmosphere, in a flame-dried 10 mL Schlenk tube. Isolated yield.

b

2a instead of 1a.

The optimized catalytic system was next applied to N-benzoyl tetrahydroisoquinoline 2a. Under the optimized KF-assisted conditions, the effect of the chlorosilane catalyst was evaluated using TMSCl (I), TBDPSCl (II), TBDMSCl (III), and TIPSCl (IV). The corresponding N,N-aminal 5a was obtained in 51, 43, 54, and 67% yields, respectively, with TIPSCl (IV) again proving to be the most effective chlorosilane catalyst (entries 17–20). Thus, the chloramine-T/TIPSCl/KF combination was identified as the optimal catalytic system for the direct α-C(sp3)–H amination of both cyclic benzylic ethers and amines.

With the optimized TIPSCl/KF catalytic system in hand, we examined the substrate scope for the direct α-C(sp3)–H amination of cyclic benzylic ethers and amines (Scheme 2).

Scheme 2. Substrate scope.a aReaction conditions: 1 or 2 (0.5 mmol), 3 (1.2 equiv.), TIPSCl (IV, 20 mol%), KF (2 equiv.), CH3CN (0.2 M, 2.5 mL), 24 h, rt. Isolated yield. bAttempted extension to an acyclic ether; no appreciable reaction was observed.

Scheme 2

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Isochroman was first examined as a representative O-heterocycle, affording N,O-aminal 4a in quantitative yield. Halogen-, alkyl-, and methoxy-substituted isochromans were all well tolerated, affording 4b–4i in moderate to high yields. Variation in the O-heterocyclic ring size (1,3-dihydroisobenzofuran), benzylic substitution, and aromatic ring extension were likewise well tolerated, affording 4j–4m in synthetically useful yields. These results demonstrate the broad applicability of the chloramine-T/TIPSCl/KF catalytic system for direct α-C(sp3)–H amination of cyclic benzylic ethers. In contrast, benzyl methyl ether, a representative acyclic benzylic ether, showed no appreciable reactivity under the standard conditions (4n), indicating limited applicability of the present catalytic system to acyclic ether substrates.

We next examined the applicability of the optimized catalytic system to cyclic benzylic amines for N,N-aminal formation. N-Benzoyl tetrahydroisoquinoline afforded 5a in good yield, while a p-fluorobenzoyl protecting group further improved the reaction efficiency (5b). Electron-rich and electron-deficient aryl substituents on the tetrahydroisoquinoline backbone were well tolerated, providing 5c–5f in generally high yields. Diverse N-protecting groups, including fluorinated, perfluoroaryl, and methoxy-substituted benzoyl, furnished 5g–5j in moderate to good yields. Carbamate-protected substrates bearing 2,2,2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc) groups also underwent the transformation to afford 5k–5m, although bulkier carbamates resulted in diminished yields.

Sulfonyl-protected substrates and an additional cyclic benzylic amine scaffold likewise proved compatible, affording 5n–5p. These results establish the chloramine-T/TIPSCl/KF catalytic system as a versatile and efficient platform for the direct benzylic C(sp3)–H amination of cyclic benzylic amines, providing straightforward access to structurally diverse N,N-aminals. To probe the reaction mechanism, a series of control experiments was conducted to investigate the C–H activation process, the involvement of radical intermediates, the role of light, and the identity of the active aminating species (Scheme 3). Deuterium-labeling experiments were first performed using [D2]-1a (Scheme 3a). In Path I, aqueous sodium thiosulfate (Na2S2O3) was added during the reaction under standard conditions, and [D1]-4a was not detected. As proposed in Scheme 4, HAT from isochroman 1a by the N-centered radical 9 generates the α-oxy carbon radical 1a′, which subsequently reacts with chlorine radical 10 to form α-oxy chloride 1a″. Chlorine radicals may undergo recombination to form Cl2,56 and Na2S2O3 is known to consume chlorine effectively.57 Thus, the presence of Na2S2O3 during the reaction could interfere with the reactive chlorine species involved in the conversion of 1a′ to 1a″, thereby inhibiting formation of oxocarbenium ion 11 and the subsequent aminated product. In contrast, when the reaction was conducted under the standard conditions and subsequently quenched with D2O, [D2]-4a was obtained in 80% yield (Path II), consistent with the formation of an N-silyl sulfonamide (R3SiNDTs) intermediate prior to the final desilylation step. Thus, the result of Path I is consistent with the involvement of reactive chlorine species in the formation of the oxocarbenium intermediate, whereas Path II supports the intermediacy of an N-silyl sulfonamide prior to desilylation step.

Scheme 3. Mechanistic studies and control experiments.

Scheme 3

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Scheme 4. Proposed catalytic pathways for the α-C(sp3)–H amination of cyclic benzylic ethers in the absence and presence of KF.

Scheme 4

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The involvement of radical intermediates was examined using radical scavengers (Scheme 3b). Under the standard conditions, 4a was obtained in 81% yield, whereas the addition of TEMPO or 1,4-dinitrobenzene reduced the yield to 51% and 47%, respectively. No product was detected in the presence of galvinoxyl. Radical adducts derived from TEMPO and galvinoxyl were detected by high-resolution mass spectrometry (HRMS), providing direct evidence for the involvement of radical intermediates. The inhibition observed in the presence of TEMPO and galvinoxyl is also consistent with interception of the radical pathway and may additionally reflect competition with the hydrogen atom transfer (HAT) step responsible for benzylic C–H activation.

The role of light was evaluated under different irradiation conditions (Scheme 3c). Performing the reaction in the dark afforded 4a in only 27% yield, which was nearly identical to that obtained in the absence of the silicon catalyst (24%). In contrast, irradiation with a fume hood lamp, blue LED, or white LED afforded comparable yields (77–81%), indicating that photoactivation of the silicon catalyst is required, whereas the reaction efficiency is largely independent of the wavelength of the visible-light source. The desilylation step was investigated independently using TIPS-protected p-toluenesulfonamide (Scheme 3d). Treatment of 6 with tetrabutylammonium chloride (TBACl) afforded p-toluenesulfonamide (7, p-TSA), demonstrating that chloride efficiently promotes Si–N bond cleavage. This result provides further support for the intermediacy of an N-silyl sulfonamide prior to the final desilylation step. On the basis of these experimental observations, a possible reaction mechanism is proposed in Scheme 4. In the absence of KF, reaction of silyl chloride (IV) with chloramine-T generates the corresponding N-silyl N-chlorosulfonamide 8, accompanied by precipitation of NaCl (Scheme 4, top). UV-vis analysis of chloramine-T in the presence of TIPSCl showed a broad absorption feature at approximately 240–270 nm compared with chloramine-T alone (Fig. S2). Although this absorption does not significantly overlap with the emission range of the fume hood lamp (315–700 nm), weak long-wavelength absorption or excitation of transient species generated under the reaction conditions may contribute to photochemical initiation over the prolonged reaction period. The marked decrease in product yield under dark conditions (Scheme 3c), together with the radical inhibition experiments (Scheme 3b), supports a light-assisted radical pathway. N–Cl bond homolysis of 8 is proposed to generate the N-centered radical 9 and chlorine radical 10.

The resulting N-centered radical 9 is proposed to mediate benzylic C–H activation of isochroman 1a through hydrogen-atom transfer (HAT), producing an α-oxy carbon radical 1a′. Subsequent radical recombination with the chlorine radical 10 affords 1-chloroisochroman 1a′′, which undergoes ionization to generate the corresponding oxocarbenium ion 11. Nucleophilic attack of chloride on the N-silyl sulfonamide 6 generates pentavalent silicate 12, which subsequently undergoes Si–N bond cleavage to release the corresponding sulfonamide.

The liberated sulfonamide then reacts with the oxocarbenium ion 11 to furnish the desired product 4a while regenerating the silyl catalyst (IV). The independent desilylation experiment (Scheme 3d) further supports the proposed chloride-mediated Si–N bond cleavage during catalyst turnover.

In the presence of KF, the catalytic cycle is proposed to proceed through a related pathway (Scheme 4, bottom). Fluoride initially converts R3SiCl (IV) into R3SiF 13, as confirmed by 19F NMR (Scheme S1). The in situ-generated R3SiF then reacts with chloramine-T to form the corresponding pentacoordinate fluorosilicate species 14. UV-vis analysis of chloramine-T in the presence of TIPSF showed a similar broad absorption feature at approximately 240–270 nm (Fig. S2), indicating an interaction between chloramine-T and the fluorosilane species. N–Cl bond homolysis followed by radical-mediated benzylic C–H activation is proposed to generate the corresponding N-silyl fluorosulfonamide intermediate 15. Intramolecular hydrogen bonding is proposed for both 12 and 15, involving an N–H⋯Cl interaction in 12 and an N–H⋯F interaction in 15, respectively. In the fluoride-containing silicate 15, fluoride coordination provides a hypervalent silicon environment that, along with the proposed N–H⋯F interaction, could promote polarization of the Si–N bond and facilitate its cleavage. Release of the sulfonamide followed by reaction with oxocarbenium ion 11 furnishes 4a and regenerates silicon catalyst 13. A possible reaction mechanism for the synthesis of N,N-aminals, proceeding through an iminium ion intermediate rather than oxocarbenium ion 11, is described in the SI (Scheme S2).

Conclusions

In summary, we have established a fluoride-activated silicon catalytic system that enables radical benzylic C(sp3)–H amination using bench-stable chloramine-T under transition-metal-free conditions. Mechanistic investigations reveal that fluoride activation fundamentally alters the reactivity of silicon, generating catalytically competent hypervalent silicon species that promote N-silyl sulfonamide formation, radical-mediated benzylic C–H activation, and oxocarbenium or iminium ion generation. Beyond elucidating the mechanism of silicon-mediated C–H amination, this work broadens the scope of fluoride-activated silicon catalysis and establishes its versatility for sustainable catalytic C(sp3)–H functionalization and late-stage molecular diversification.

Author contributions

G. H. Kim, H. Byeon, and D. W. Kim led and conducted the experiments, prepared the original draft of the manuscript, and wrote the SI. D. W. Kim performed the experiments and contributed to the writing of the SI. J. W. Yang contributed to the original draft and carried out critical review and editing, and was responsible for project supervision, conceptualization and funding acquisition.

Conflicts of interest

The authors declare no conflicts of interest.

Supplementary Material

SC-OLF-D6SC06229F-s001

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2026-25478335 and RS-2023-00219859). Additionally, the generous support of Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (RS-2022-NF000854) is gratefully acknowledged.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: detailed experimental procedures, characterization data, and copies of the 1H, 13C and 19F NMR spectra. See DOI: https://doi.org/10.1039/d6sc06229f.

Notes and references

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SC-OLF-D6SC06229F-s001
SC-OLF-D6SC06229F-s001.pdf (8.9MB, pdf)

Data Availability Statement

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: detailed experimental procedures, characterization data, and copies of the 1H, 13C and 19F NMR spectra. See DOI: https://doi.org/10.1039/d6sc06229f.

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