# Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis

Peng Wu, Gabriel Goujon, Shulei Pan, Béatrice Tuccio, Bruce Pégot, Guillaume Dagousset, Elsa Anselmi, Emmanuel Magnier, Carsten Bolm

► To cite this version:

Peng Wu, Gabriel Goujon, Shulei Pan, Béatrice Tuccio, Bruce Pégot, et al. Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis. Angewandte Chemie International Edition, 2024, 10.1002/anie.202412418. [hal-04785277](https://hal.science/hal-04785277v1)

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Submitted on 22 May 2025

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## Photocatalysis

How to cite: Angew. Chem. Int. Ed. 2024, 63, e202412418
doi.org/10.1002/anie.202412418

# Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis

Peng Wu, Gabriel Goujon, Shulei Pan, Béatrice Tuccio, Bruce Pégot, Guillaume Dagousset, Elsa Anselmi,* Emmanuel Magnier,* and Carsten Bolm*

**Abstract:** Benzo[1,3,2]dithiazole-1,1,3-trioxides are bench-stable and easy-to-use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N-Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale-up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single-electron transfer (SET) pathway induced by photoredox catalysis.

## Introduction

The “magic methyl effect” refers to the significantly enhanced biological activities of a pharmaceutical compound through the modification of its pharmacokinetic properties and metabolism upon introduction of a methyl group.[1] Such remarkable changes have been demonstrated in numerous instances, as, for example, in protein ligand binding[2] and a

potency improvement of an S1P₁ antagonist[3] (Scheme 1A, top). Also, the deuterium kinetic isotope effect allows a drug improvement. Because the C–D bond exhibits a lower chemical reactivity compared to the C–H bond, the incorporation of deuterium atoms into clinical drug candidates can result in an enhanced efficacy while suppressing side effects.[4] Two typical examples of approved drugs containing trideuteriomethyl (CD₃) groups are depicted at the bottom of Scheme 1A.[5]

Conventional methylating agents ranging from electrophilic methyl halides and Me₂SO₄ to nucleophilic organometallic reagents and methyl boranes often encounter issues such as acute toxicity, explosion risk, flammability, volatility, and limited reactivity.[6] As valuable alternatives, methyl radical strategies have recently attracted attention. In particular those involving photochemical methyl radical generations are esteemed for their mild reaction conditions, robustness, simplicity, and additional merits.[7] Various methylation reagents can be activated by visible light.

<figure><img src="image_2.png" /></figure>

© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

### A) The magic methyl effect and approved drugs containing CD₃ fragments

<figure><img src="image_3.png" /><figcaption>Inhibitor of p38α MAP kinase</figcaption></figure>

$$R = H, K > 2500$$

$$R = Me, K = 12$$

<figure><img src="image_4.png" /><figcaption>Austedo (SD-809)</figcaption></figure>

FDA-approval for the treatment of chorea associated with Huntington's disease

<figure><img src="image_5.png" /><figcaption>S1P₁ antagonist</figcaption></figure>

$$R^{1} = Cl, R^{2} = H \rightarrow R^{1} = R^{2} = Me$$

> 2000-fold potency boost

<figure><img src="image_6.png" /><figcaption>Donafenib</figcaption></figure>

First approval in China for unresectable hepatocellular cancer

### B) Benzo[1,3,2]dithiazole-1,1,3-trioxides as CH₃- and CD₃-radical sources and their applications under photoredox catalysis

**This work**

<figure><img src="image_7.png" /><figcaption>**Scheme 1.** A) The magic methyl effect and approved CD₃-containing drugs containing CD₃ fragments. B) The reagents and transformations reported here. In parentheses: percentage of D-incorporation.</figcaption></figure>

<footnote>[*] Dr. P. Wu, S. Pan, Prof. Dr. C. Bolm
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
Homepage: https://bolm.oc.rwth-aachen.de/

G. Goujon, Dr. B. Pégot, Dr. G. Dagousset, Dr. E. Anselmi,
Dr. E. Magnier
Institut Lavoisier de Versailles
Université Paris-Saclay
78000, Versailles, France
E-mail: elsa.anselmi@univ-tours.fr
emmanuel.magnier@uvsq.fr

Dr. E. Anselmi
Université de Tours, Faculté des Sciences et Techniques, 37200
Tours, France

Prof. B. Tuccio
Aix-Marseille Université
CNRS, Institut de Chimie Radicaire, UMR 7273,
F-13397 Marseille Cedex 20, France</footnote>
However, many prevalent cases involve unstable peroxides or oxides such as tBuOOOMe (TBPA), tBuOOtBu (DTBP), (MeCO₂)₂, and PhI(OAc)₂, which pose challenges in selectivity, storage and carry an inherent risk of explosion.[⁸]

Although also MeOH[⁹] and DMSO[¹⁰] are effective methylation reagents, their application is mostly confined to C–H methylation reactions of heterocycles and alkanes. In addition, several other methylation reagents have been developed, including acetic acid and its derivatives,[¹¹] gaseous methane,[¹²] trimethyl orthoformate,[¹³] TsOMe,[¹⁴] TMEDA,[¹⁵] and others.[¹⁶] Intriguingly, many of these methylation reagents have a limited range of applications and, in some cases, they also require oxidizing,[¹⁶b] or reducing[¹⁴b] conditions. Furthermore, light-induced CD₃ radical-generating reagents are comparatively scarce,[¹⁰a,11f,16d,17] and because many methylation reagents lack the corresponding CD₃ counterparts, the development of versatile reagents that can serve as precursors for both CH₃ and CD₃ radicals is of great interest.

In recent decades, fluoroalkyl sulfoximines have found wide use as fluoroalkyl radical sources in photochemical reactions by single-electron transfer (SET) processes.[¹⁸,¹⁹] However, to best of our knowledge, there are no reports on the utilization of *S*-alkyl sulfoximines as methyl or alkyl radical sources under photochemical conditions.

In light of this research background and considering the expertise of our two research groups in sulfur chemistry, we decided to join forces and to focus our attention on the search and development of novel methylation and perdeuteromethylation reagents with cyclic sulfoximine frameworks. Recently, two approaches towards benzo-[1,3,2]dithiazole-1-oxides **1** were reported independently. First, cyclic fluoro sulfoximines (CF₃, CF₂H, CFH₂) were accessed by a multi-step synthesis involving a coupling of a thiosugar with an *S*-aryl sulfoximine followed by cyclization under oxidative conditions.[²⁰] The second synthesis made use of a copper-catalyzed cross-coupling reaction of 2-bromophenyl sulfoximines and elemental sulfur (S₈), leading to a series of highly functionalized benzo[1,3,2]dithiazole-1-oxides including those with *S*-alkyl groups.[²¹] For the study described here (Scheme 1B), product **1a** proved to be the key compound. Its subsequent derivatization gave bench-stable and easy-to-use (deutero)methyl radical transfer agent **2a**. Perdeuteromethylations became possible using CD₃-containing analog **d₃-2a**. Compared to other methylation reagents, which have limited applications in photo-chemistry, **2a** and **d₃-2a** revealed a broad reactivity with a variety of radical acceptors (Scheme 1B).

## Results and Discussion

As shown in Scheme 1B, key 1,1,3-trioxide **2a** can be prepared by oxidation of *S*-methyl benzo[1,3,2]dithiazole-1-oxide (**1a**) with *m*-CPBA in almost quantitative yield. Our robust and scalable synthesis allow the two-step preparation of compound **2a** on multigram scale (up to 8 g batch). The X-ray crystal structure of **2a** is shown in Figure 1.[²²] It

exhibits a three-dimensional heterocycle having two sulfur atoms with tetrahedron geometry.

To our delight, treatment of **2a** with a combination of D₂O and NEt₃ results in smooth and easy H/D-exchange providing **d₃-2a** in essentially quantitative yield with a 98 % deuterium incorporation (Scheme 1B and Supporting Information for experimental details).[²³]

Following preliminary observations, the study of the methylation reaction with **2a** as methyl radical source was initiated by investigating the basic requirements for difunctionalizations of styrenes. Using 4-vinyl biphenyl (**3a**) as representative substrate, methyl radical addition to **3a** followed by reaction with methanol was expected to lead to methyl ether **4a**. Table 1 summarizes the most relevant results.

Under blue light irradiation, the effects of various photocatalysts (applied in a quantity of 1 mol %) were tested first. With *fac*-Ir(ppy)₃ in MeOH, **4a** was obtained in 36 % yield (Table 1, entry 1). Neither Ru(bpy)₂Cl₂ nor Ir(dtbppy)-(ppy)₂PF₆ led to product formation (Table 1, entries 2 and 3). Attempting to address the limited solubility of **2a** in methanol, mixed solvent systems were then applied (Table 1, entries 4–6). In this manner, the yield of **4a** could be raised to 50 % by using a 1:1 mixture of DCM and MeOH (Table 1, entry 4).

Next, the investigation delved into the impact of bases as additives (Table 1, entries 7–10). Among DABCO, NEt₃, TMEDA, and DIPEA, triethylamine proved best affording **4a** in 80 % yield after column chromatography (Table 1, entry 8). When the reaction was carried out in the dark or under aerobic conditions, **4a** was not formed at all or obtained in 56 % yield, respectively (Table 1, entries 11 and 12). No product was observed when the photocatalyst was absent (Table 1, entry 13). In the presence of 2,2,6,6-tetramethylpiperidinooxy (TEMPO) as radical scavenger only a trace amount of the product was observed (Table 1, entry 14). The detection of a TEMPO-trapped adduct by ESI-MS analysis suggested the involvement of a radical process. (For further details, see the mechanistic discussion and the Supporting Information).

The very particular properties of **2a** became apparent in attempts to apply compounds with related structures (Table 1, entry 15). Neither methylphenylsulfone (**Me-1**) nor *N*-substituted *S*-phenyl *S*-methyl sulfoximines **Me-2–Me-5** gave more than traces of **4a**. In this series, the result for *N*-Ts sulfoximine **Me-4** is particularly noteworthy because fluorinated analogs of **Me-4** are very well known to be effective CF₃, CF₂H, and CH₂F radical sources.[¹⁸e–g,²⁴] The importance of the SO₂ fragment of **2a** was revealed by

<figure><img src="image_8.png" /><figcaption>**Figure 1.** X-ray crystal structure of **2a**.</figcaption></figure>
<table><caption>**Table 1:** Investigation of the reaction conditions.[a]</caption><thead><tr><th colspan="7">Other potential methylation reagents:</th></tr><tr><th>Entry</th><th>Me-1 n.d.</th><th>Solvent</th><th>Photocatalyst</th><th>Additive</th><th>Yield of 4a [%]<sup>b</sup></th></tr></thead><tbody><tr><td>1</td><td>MeOH</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>/</td><td>36</td></tr><tr><td>2</td><td>MeOH</td><td></td><td>Ru(bpy)<sub>3</sub>Cl<sub>2</sub></td><td>/</td><td>0</td></tr><tr><td>3</td><td>MeOH</td><td></td><td>Ir(dtbppy)(ppy)<sub>2</sub>PF<sub>6</sub></td><td>/</td><td>0</td></tr><tr><td>4</td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>/</td><td>50</td></tr><tr><td>5</td><td>acetone/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>/</td><td>48</td></tr><tr><td>6</td><td>MeCN/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>/</td><td>44</td></tr><tr><td>7</td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>DABCO</td><td>78</td></tr><tr><td>8</td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>NET<sub>3</sub></td><td>82 (80)</td></tr><tr><td>9</td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>TMEDA</td><td>70</td></tr><tr><td>10</td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>DIPEA</td><td>77</td></tr><tr><td>11<sup>[c]</sup></td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>NET<sub>3</sub></td><td>0</td></tr><tr><td>12<sup>[d]</sup></td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>NET<sub>3</sub></td><td>56</td></tr><tr><td>13</td><td>DCM/MeOH (1/1)</td><td>/</td><td></td><td>NET<sub>3</sub></td><td>0</td></tr><tr><td>14<sup>[e]</sup></td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>NET<sub>3</sub></td><td>trace</td></tr><tr><td>15<sup>[f]</sup></td><td>DCM/MeOH (1/1)</td><td></td><td>fac-Ir(ppy)<sub>3</sub></td><td>NET<sub>3</sub></td><td>0-51</td></tr></tbody></table>

[a] Reaction conditions: **2a** (0.1 mmol), **3a** (0.2 mmol), photocatalyst (1 mol%), and additive (0.1 mmol) in the solvent (2.0 mL) were irradiated with blue light under argon atmosphere at room temperature for 12 h. n.d. = not detected. [b] Determined by ¹H NMR spectroscopy using CH₂Br₂ as internal standard; in parentheses, yield after isolation by column chromatography. [c] In the dark. [d] Performed in air. [e] In the presence of TEMPO (1.5 equiv.). [f] Using of other potential methylation reagents instead of **2a**.

testing **1a** and **Me-6** as methyl radical donor. While the former provided inactive leading to only a trace of **4a**, the latter oxide led to **4a** in 51% yield. Apparently, the electronic properties of the second sulfur in the ring system had a great impact on the effectiveness of the methyl radical formation.

With the optimized reaction conditions established (Table 1, entry 8), the substrate scope was elaborated. The results are shown in Scheme 2.

First, styrene derivatives **3** were tested. In general, the process was characterized by a good tolerance towards various functional groups. In substrates with a single aryl group, carboxyl, thiomethyl, dimethylamino, naphthyl, and cyclic diether substituents were well tolerated providing products **4a-i** in moderate to good yields.[25] 1,1-Disubstituted styrene derivatives were applicable under standard reaction conditions as well, affording products **4j-l** in yields of 68-84%. Other terminal and conjugated olefins, including 1,3-dienes **3m** and **3n**, 1,3-enynes **3o** and **3p**, and N-vinylarylamide **3q**, exhibited favorable selectivity and reactivity also, leading to the corresponding desired products **4m-q** in yields ranging from 33-68%. Attempts to use unactivated olefins, alkynes, and allenes remained unsuccessful

identifying the limitations of the process (for further details, see the Supporting Information).

Wondering if the substrate scope could be extended by additions of other alkyl groups than methyl, 1,1,3-trioxides **2b-d** were prepared and tested in additions to vinyl biphenyl **3a** as reaction partner. Pleasingly, those reactions proceeded well too, resulting in the desired products **4r**, **4s**, and **4t** in good yields (75%, 71%, and 74%, respectively).

Substituting MeOH in reactions with **2a** and **3a** by H₂O or EtOH led to the corresponding products in yields of 48% (**4u**) and 62% (**4v**). In the case of H₂O, a mixed solvent of acetone/H₂O (3:1) was employed. Additionally, applying isoborneol and estrone derivatives as more functionalized substrates afforded **4w** and **4s** in 74% and 64% yield, respectively.

Encouraged by the successful styrene difunctionalizations, we started wondering about the use of reagents **2** in other reactions (Scheme 2). First, N-aryl acrylamides **6** were tested with the vision to perform a radical addition followed by cyclization to give products of type **7**. The reactions exhibited a robust substrate compatibility, effectively accommodating both electron-withdrawing and -donating substituents on the arene (products **7a-f**).

Except for NH-derivative **6j**, where product **7j** was not detected (n.d.), acrylamides with various N-substituents reacted well (products **7g-i**). Next, C-H methylation reactions of quinoxalinos **8** were tested. A range of N-substituents (including NH) were tolerated, and the corresponding products (**9a-d**) were obtained in yields ranging from 63% to 82%.

Reacting **2a** with 2-isocyanobiphenyl (**10**) gave 6-methylphenanthridine (**11**) in 63% yield. Ketone **13** was obtained in 70% yield when **2a** reacted with enol silane **12**. Finally, involving a Truce-Smiles rearrangement N-Ts acrylamide **14** gave **15** in 19% yield upon reaction with **2a**. Of note, in all of the aforementioned alkylations with 1,1,3-trioxides **2**, salt **5** was detected as byproduct (in quantitative yield as determined by ¹H NMR analysis of the crude mixture). Pleasingly, this scaffold was recovered in >90%. This is, to the best of our knowledge, a first in the chemistry of sulfoximines used as reagents, and is a major advantage in terms of the environment concerns and atom economy, as we were also able to recycle the skeleton (see Scheme 3D).

As assumed, perdeuteromethylations with **d₃-2a** proceeded equally well as the analogous methylations with **2a**. This hypothesis was confirmed in five representative transformations (Scheme 3A). First, a deuteromethoxy/perdeuteromethylation was achieved by subjecting 4-vinylbiphenyl (**3a**) to **d₃-2a** (with 98% D incorporation) under the standard reaction conditions (Table 1, entry 8) using a mixture of CD₃OD/DCM (1/1) as solvent. As a result, **d₆-4a** was obtained in 76% yield with a deuteration degree of 96%. Cyclization reactions of **6h** and **10** gave 74% of **d₃-7h** and 65% of **d₃-11** with deuteration incorporations of 94% and 85%, respectively. The C-H perdeuteromethylation of **8b** led to **d₃-9b** in 59% yield with a D degree of 50%. Reacting enol silane **12** with **d₃-2a** afforded 68% of ketone **d₃-13** with 93% of deuteration. The relatively low D-values of **d₃-11** (85%) and **d₃-9b** (50%) may be due to the high
<figure><img src="image_9.png" /></figure>

2 (0.1 mmol)

<figure><img src="image_10.png" /></figure>

3 (0.2 mmol)

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /></figure>

2a R = Me

2b R = nPr

2c R = iPr

2d R = Cy

4

5

alkoxy/hydroxy alkylations of styrenes

<figure><img src="image_15.png" /></figure>

4a 80%

<figure><img src="image_16.png" /></figure>

4b 84%

<figure><img src="image_17.png" /></figure>

4c 61%

<figure><img src="image_18.png" /></figure>

4d 33%

<figure><img src="image_19.png" /></figure>

4e 72%

<figure><img src="image_20.png" /></figure>

4f 43%

<figure><img src="image_21.png" /></figure>

4g 73%

<figure><img src="image_22.png" /></figure>

4h 67%

<figure><img src="image_23.png" /></figure>

4i 78%

<figure><img src="image_24.png" /></figure>

4j 83%

<figure><img src="image_25.png" /></figure>

4k 68%

<figure><img src="image_26.png" /></figure>

4l 84%

<figure><img src="image_27.png" /></figure>

4m 47%

<figure><img src="image_28.png" /></figure>

4n 33%

<figure><img src="image_29.png" /></figure>

4o 56%

<figure><img src="image_30.png" /></figure>

4p 68%

<figure><img src="image_31.png" /></figure>

<figure><img src="image_32.png" /></figure>

<figure><img src="image_33.png" /></figure>

4s 71%

<figure><img src="image_34.png" /></figure>

4t 74%

<figure><img src="image_35.png" /></figure>

4u 48%[b]

<figure><img src="image_36.png" /></figure>

4v 62%

<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /></figure>

from DL-Isoborneol

4w 74%

from Estrone

4s 64%

cyclizations of acrylamides

<figure><img src="image_39.png" /></figure>

2a (0.1 mmol)

(ii)

<figure><img src="image_40.png" /></figure>

6 (0.2 mmol)

7

<figure><img src="image_41.png" /></figure>

7e 85%

<figure><img src="image_42.png" /></figure>

7f 65%

<figure><img src="image_43.png" /></figure>

7a 81%

<figure><img src="image_44.png" /></figure>

7b 78%

<figure><img src="image_45.png" /></figure>

7c 71%

<figure><img src="image_46.png" /></figure>

7d 73%

<figure><img src="image_47.png" /></figure>

7g 76%

<figure><img src="image_48.png" /></figure>

7h 83%

<figure><img src="image_49.png" /></figure>

7i 63%

<figure><img src="image_50.png" /></figure>

7j n.d.

further transformations

<figure><img src="image_51.png" /></figure>

2a (0.1 mmol)

(iii)

C-H methylation

8 (0.2 mmol)

<figure><img src="image_52.png" /></figure>

9

<figure><img src="image_53.png" /></figure>

9a 63%

<figure><img src="image_54.png" /></figure>

9b 69%

<figure><img src="image_55.png" /></figure>

9c 82%

<figure><img src="image_56.png" /></figure>

9d 74%

<figure><img src="image_57.png" /></figure>

10 (0.15 mmol)

<figure><img src="image_58.png" /></figure>

<figure><img src="image_59.png" /></figure>

11 63%

<figure><img src="image_60.png" /></figure>

<figure><img src="image_61.png" /></figure>

<figure><img src="image_62.png" /></figure>

12 (0.25 mmol)

13 70%

<figure><img src="image_63.png" /></figure>

<figure><img src="image_64.png" /></figure>

<figure><img src="image_65.png" /></figure>

15 19%

**Scheme 2.** Reaction conditions: **2** (0.1 mmol), **3** (0.2 mmol), *fac*-Ir(ppy)₃ (1 mol%), *NEt*₃ (0.1 mmol), and DCM/MeOH (2 mL, 1/1) were irradiated with blue light at room temperature for 12 h. n.d. = not detected. [a] Using of MeOH (2 mL) as solvent. [b] Using of acetone/H₂O (2 mL, 3/1) as solvent. (ii) **2a**, **6**, *fac*-Ir(ppy)₃, *NEt*₃, DMC, and blue LEDs. (iii) **2a**, **8**, *fac*-Ir(ppy)₃, *NEt*₃, DMC, and blue LEDs. (iv) **2a**, **10**, *fac*-Ir(ppy)₃, *NEt*₃, DMC, and blue LEDs. (v) **2a**, **12**, *fac*-Ir(ppy)₃, *NEt*₃, DMC, and blue LEDs. (vi) **2a**, **14**, *fac*-Ir(ppy)₃, *NEt*₃, MeCN, and blue LEDs. See Supporting Information for full experimental details.

acidities of the CD₃ groups in the products resulting in fast base-assisted D/H exchange reactions with available protons in the reaction system. Because the D incorporation (less than 5%) was also low when *d*₃-*2a* was applied in an addition to **3a** performed in DCM/MeOH, we wondered if the underlying rapid H/D substitution could be utilized for introducing an in situ deuteromethoxy/perdeuteromethylation starting from non-deuterated **2a**. This hypothesis

was confirmed by the experiment depicted in Scheme 3B. Hence, when **2a** was used in combination with *NEt*₃ in DCM/CD₃OD, the H/D exchange gave *d*₃-*2a* in situ, and its reaction under standard conditions led to *d*₆-*4a* in 77% yield with a D-incorporation of 95%. An intermolecular kinetic isotope competition experiment with a 1:1 mixture of **2a** and *d*₃-*2a* adding to **6h** showed that both reagents reacted equally fast providing **7h** and *d*₃-*7h* in a 1:1 ratio.
A) The transformations of deuteromethylation reagent *d*<sub>3</sub>-2a

<figure><img src="image_66.png" /><figcaption>**Scheme 3.** A) i) The transformations of deuteromethylation reagent *d*<sub>3</sub>-2a under conditions as described in Scheme 2 for reactions with *2a*. The percentages of D-incorporation are provided in parentheses. B) In situ generation of *d*<sub>3</sub>-2a and its use in a reaction with *3a*. C) Kinetic isotope competition experiment between *2a* and *d*<sub>3</sub>-2a. D) Regeneration of reagent *2a* from the resulting salt *5*. (vi) *5*, TCCA and DCM. (vii) *16*, KF, 18-crown-6, and MeCN. (viii) *16*, PhONa and THF. (ix) *17*, MeLi, and Et<sub>2</sub>O. See Supporting Information for full experimental details.</figcaption></figure>

B) *In-situ* generation of *d*<sub>3</sub>-2a and its transformation

<figure><img src="image_67.png" /></figure>

C) Kinetic isotope competition experiment between 2a and d<sub>3</sub>-2a

<figure><img src="image_68.png" /></figure>

D) Regeneration of methylation reagent 2a from salt 5

<figure><img src="image_69.png" /></figure>

Apparently, the secondary kinetic isotope effect was small
suggesting that the S–C bond breaking event was not rate-
limiting (Scheme 3C; for further details, see the Supporting
Information).

As described before, all transformations with reagents **2**
led to salt **5** as byproduct. Our next efforts were thus
focused on a search for a regeneration protocol of **5** to give
**2a** (Scheme 3D). To our delight this became possible by
oxidative chlorination of **5** with trichloroisocyanuric acid
(TCCA) to provide cyclic sulfoximidoyl chloride **16**, which
proved highly valuable for the subsequent finalization of the
recycling process. Thus, treatment of **16** with KF/18-crown-6
gave sulfoximidoyl fluoride **17**, which upon reaction with
methyl lithium led to **2a** in 46% yield.[26] The attempt to
establish an alternative pathway via sulfonimidate **18**, which
was accessible by reaction of **16** with PhONa, remained
unsuccessful. Neither MeLi nor MeMgBr was capable of
converting **18** into targeted **2a**. (Additional reactions along
this line are summarized in the Supporting Information.)

With the aim to develop a practical scale-up protocol,
the next experiments were performed in a photoflow
reactor. The results are summarized in Table 2. Using the
batch procedure as starting point, **2a**, **3a**, NEt₃, and a
catalytic amount of *fac*-Ir(ppy)₃ were combined in a 1:1
mixture of MeOH and DCM. Varying the flow rate had an
impact on the reaction outcome with an increase in yield for
**4a** from 62% to 78% when changing the flow rate from
0.25 mL/min to 0.5 mL/min (Table 2, entries 1 and 2). At

0.75 mL/min, the yield remained essentially unchanged
(77% of **4a**, Table 2, entry 3) and it decreased at 1 mL/min
(67% of **4a**, Table 2, entry 4). Consequently, the subsequent
5 mmol reaction was performed at an intermediate rate of
0.5 mL/min, and to our delight, product **4a** was formed in
84% yield (Table 2, entry 5), confirming the feasibility of
working on larger scales. The results on 0.1 mmol were
comparable in flow and in batch (~80% in the two cases),
but on larger scale, flow procedure seems consistent while
the experiment in batch shows a decrease of the yield
(Table 2, entry 6).

In order to gain mechanistic insight, a series of
physicochemical data were determined. As demonstrated
before (Table 1, entries 11 and 13), both light and the
iridium photocatalyst were required for the reaction to
proceed suggesting a radical-based mechanism. EPR/spin
trapping experiments were performed to demonstrate the
release of the methyl radical. Several attempts were carried
out using different spin traps and operating conditions (see
Supporting Information for details). In each case, the methyl
donor **2a** was placed in the presence of *fac*-Ir(ppy)₃
(1 mol%) and a spin trap (100 mM), then irradiated with a
blue LED. To illustrate these experiments, Figure 2a shows
the EPR spectra obtained in deoxygenated dimeth-
ylcarbamate using PBN or DMPO spin traps. Their com-
puter simulation (Figure 2a, red dotted lines) yielded the
hyperfine coupling constant values, which were then com-
pared with literature data in order to identify the trapped
<table><caption>**Table 2:** Methoxy methylation reaction in a photoflow reactor.</caption><thead><tr><th>Entry</th><th>Scale</th><th>Flow rate [mL/min]</th><th>Yield of 4a [%]<sup>[a]</sup></th></tr></thead><tbody><tr><td>1</td><td>0.1 mmol</td><td>0.25</td><td>62</td></tr><tr><td>2</td><td>0.1 mmol</td><td>0.50</td><td>78</td></tr><tr><td>3</td><td>0.1 mmol</td><td>0.75</td><td>77</td></tr><tr><td>4</td><td>0.1 mmol</td><td>1</td><td>67</td></tr><tr><td>5</td><td>5.0 mmol</td><td>0.5 (residence time = 20 min)</td><td>76 (84)</td></tr><tr><td>6<sup>[b]</sup></td><td>5.0 mmol</td><td>/</td><td>54</td></tr></tbody></table>

[a] Determined by ¹H NMR spectroscopy using 1,1,2,2-tetrachloroethane as internal standard; in parentheses, yield after isolation by column chromatography. [b] Reaction performed in batch in the standard conditions during 16 h.

<figure><img src="image_70.png" /><figcaption>**Figure 2.** a) EPR spectrum of PBN–Me formed after blue LED irradiation of a solution containing 2a, *fac*-Ir(ppy)₃ and the nitrone PBN, and its superimposed simulation; EPR spectrum of obtained after blue LED irradiation of a solution containing 2a, *fac*-Ir(ppy)₃ and the nitrone DMPO, and its superimposed simulation; the six lines topped by a cross corresponds to the DMPO–Me adduct; b) Stern–Volmer experiment in DCM/MeOH (1:1); c) Kinetic study of the reaction for quantum yield measurement. See Supporting Information for full experimental details.</figcaption></figure>

radical.[27] With PBN spin trap, the six line EPR spectrum observed could be assigned to the PBN–Me adduct, based on its hyperfine coupling constants hfcc values ($a_N$=14.7 G and $a_{Hβ}$=3.5 G). The slightly more complex signal obtained with DMPO nitrone shows the presence of two para-magnetic species. The first one exhibits hyperfine coupling constants characteristic of the DMPO–Me adduct ($a_N$=14.8 G and $a_{Hβ}$=21.0 G, 55%), while the second one could correspond to the DMPO-OMe adduct, which may be the result of a reaction between the experimental solvent DMC and the DMPO spin trap ($a_N$=13 G, $a_{Hβ}$=7.1 G and $a_{Hγ}$=1.7 G, 45%). As no EPR signal was obtained in the blank tests carried out in the absence of catalyst, light or substrate,

we can conclude that the methyl radical is indeed released from compound 2a in these experiments.

An additional assay performed in the presence of 2a, *fac*-Ir(ppy)₃ and substrate 3a, in the presence of the nitroso spin trap MNP, led to detect the MNP-adduct of a carbon-centered secondary radical formed after addition of the methyl radical to the substrate ($a_N$=16.0 G and $a_{Hβ}$=3.9 G; see Supporting Information for details). Taken together, all these spin trapping results undoubtedly confirm the radical nature of the mechanism.

Measuring the reduction potential of 2a gave a value of $E^°$=−1.72 V vs. SCE (see SI), which was close to the one for *fac*-Ir(ppy)₃ ($E^°$=−1.73 V vs. SCE) indicating that a SET reduction of 2a by the excited state *fac*-Ir*(ppy)₃ was feasible. To confirm this hypothesis, luminescence quenching experiments (Figure 2b) showed that 2a was the only species that efficiently quenched the luminescence of excited *fac*-Ir*(ppy)₃, with a quenching rate coefficient $k_q$=40.5×10⁶ L·mol⁻¹·s⁻¹. The quantum yield of the reaction was determined (Figure 2c). Being lower than 1, the found value of $Φ$≤0.55 suggested that the photocatalytic process was most probably the major pathway of the reaction, even though a chain mechanism could not be completely ruled out.

With this information, we propose a mechanism (Figure 3) starting with the photoexcitation of the iridium

<figure><img src="image_71.png" /><figcaption>**Figure 3.** Proposed mechanism for the methoxymethylation of alkene 3 with 2a to give product 4.</figcaption></figure>
catalyst. Single-electron transfer (SET) from the resulting excited Ir\* species to sulfoximine **2a** gives a methyl radical and anion **A**. Addition of the methyl radical onto alkene **3** results in radical **B**, which subsequently undergoes a SET oxidation to form the corresponding cation **C**. Finally, **C** reacts with MeOH, and deprotonation with the base gives product **4** and ammonium species **D**. Combination of the latter with anion **A** leads to salt **5**.

## Conclusions

In summary, we developed novel bench-stable and easy-to-use reagents for the generation of methyl and perdeuteromethyl radicals under photoredox catalysis. Using these reagents allows to add methyl and perdeuteromethyl groups to a wide range of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanates, silyl enol ethers, and N-Ts acrylamide. After the reaction, a salt from the starting material can be isolated and used to regenerate the original reagent. For the up-scaling of the (perdeutero)methylation, a photoflow reactor has been utilized. The results of various physicochemical experiments suggest a photoredox mechanism.

## Acknowledgements

We are indebted to RWTH Aachen University for generous research funding and infrastructure. P.W. and S.P. thank the CSC (China Scholarship Council) for predoctoral stipends. GG thanks the UVSQ for a PhD grant. CNRS and GIS Fluor are acknowledged for their support. BT acknowledges NIEHS for providing free the WINSIM software used to simulate the EPR spectra. Dr. Thibaut Duhail is thanked for preliminary studies and seminal results. Open Access funding enabled and organized by Projekt DEAL.

## Conflict of Interest

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article. The authors have cited additional references within the Supporting Information.[10b,21,26,28–56]

**Keywords:** flow chemistry • methylation • perdeuteromethylation photochemistry • radicals • sulfoximines

[1] a) E. J. Barreiro, A. E. Kümmerle, C. A. M. Fraga, *Chem. Rev.* **2011**, *111*, 5215–5246; b) Q. Zhang, W. A. van der Donk, W. Liu, *Acc. Chem. Res.* **2012**, *45*, 555–564; c) J. Chatterjee, F. Rechenmacher, H. Kessler, *Angew. Chem. Int. Ed.* **2013**, *52*, 254–269; d) H. Schönherr, T. Cernak, *Angew. Chem. Int. Ed.* **2013**, *52*, 12256–12267; e) S. Sun, J. Fu, *Bioorg. Med. Chem. Lett.* **2018**, *28*, 3283–3289.

[2] C. S. Leung, S. S. F. Leung, J. Tirado-Rives, W. L. Jorgensen, *J. Med. Chem.* **2012**, *55*, 4489–4500.

[3] J. Quancard, B. Bollbuck, P. Janser, D. Angst, F. Berst, P. Buehlmayer, M. Streiff, C. Beerli, V. Brinkmann, D. Guerini, P. A. Smith, T. J. Seabrook, M. Traebert, K. Seuwen, R. Hersperger, C. Bruns, F. Bassilana, M. Bigau, *Chem. Biol.* **2012**, *19*, 1142–1151.

[4] For recent overviews on applications of deuterium in durg discovery, see: a) R. M. C. DiMartino, B. D. Maxwell, T. Pirali, *Nat. Rev. Drug Discovery* **2023**, *22*, 562–584; b) H. M. Chandra Mouli, A. Vinod, S. Kumari, A. K. Tiwari, M. K. Kathiravan, V. Ravichandiran, R. Peraman, *Bioorg. Chem.* **2023**, *135*, 106490–106507; c) R. B. Kargbo, *ACS Med. Chem. Lett.* **2023**, *14*, 362–364; d) Q. Sun, J. F. Soule, *Chem. Soc. Rev.* **2021**, *50*, 10806–10835; e) T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani, *J. Med. Chem.* **2019**, *62*, 5276–5297.

[5] a) S. H. DeWitt, B. E. Maryanof, *Biochemistry* **2018**, *57*, 472–473; b) S. J. Keam, S. Duggan, *Drugs* **2021**, *81*, 1915–1920.

[6] For selected overviews on conventional methylation reagents, see: a) G. Yan, A. J. Borah, L. Wang, M. Yang, *Adv. Synth. Catal.* **2015**, *357*, 1333–1350; b) Y. Zhao, J. Bai, M. Wang, H. Lu, Z. Shi, *Sci. Sin. Chim.* **2020**, *50*, 526–551; c) D. Aynetdinau, M. C. Callens, H. B. Hicks, C. Y. X. Poh, B. D. A. Shennan, A. M. Boyd, Z. H. Lim, J. A. Leitch, D. J. Dixon, *Chem. Soc. Rev.* **2021**, *50*, 5517–5563.

[7] For recent overviews on visible light-mediated methylation reactions, see: a) Q.-Y. Li, Y. He, Y.-M. Lin, L. Gong, *Chem. Eur. J.* **2023**, e202302542; b) I. Agrawal, G. Prakash, S. A. Al-Thabaiti, M. Mokhtar, D. Maiti, *Catalysts* **2022**, *12*, 510; c) J. Huang, Z. Chen, J. Wu, *ACS Catal.* **2021**, *11*, 10713–10732; d) J. Du, Y. Chen, Z. Zuo, *Chin. J. Org. Chem.* **2020**, *40*, 3646–3655.

[8] a) D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway, M. Tudge, *Angew. Chem. Int. Ed.* **2014**, *53*, 4802–4806; b) A. Vasilopoulos, S. W. Krska, S. S. Stahl, *Science* **2021**, *372*, 398–403; c) H. Liu, Y. Wu, L. Liu, J.-T. Yu, C. Pan, *Chem. Commun.* **2023**, *59*, 8556–8559; d) W. Xue, Y. Su, K.-H. Wang, R. Zhang, Y. Feng, L. Cao, D. Huang, Y. Hu, *Org. Biomol. Chem.* **2019**, *17*, 6654–6661; e) L.-Y. Xie, L.-L. Jiang, J.-X. Tan, Y. Wang, X.-Q. Xu, B. Zhang, Z. Cao, W.-M. He, *ACS Sustainable Chem. Eng.* **2019**, *7*, 14153–14160; f) L. Zhang, J. He, P. Zhang, K. Zheng, C. Shen, *J. Mol. Catal.* **2022**, *519*, 112145.

[9] a) J. Jin, D. W. C. MacMillan, *Nature* **2015**, *525*, 87–90; b) W. Liu, Y. Yang, Z.-Z. Zhou, C.-J. Li, *Chem* **2017**, *2*, 688–702; c) B. Emayavaramban, P. Chakraborty, P. Dahiya, B. Sundararaju, *Org. Lett.* **2022**, *24*, 6219–6223; d) M. Liu, Z. Qiu, L. Tan, R. T. Rashid, S. Chu, Y. Cen, Z. Luo, R. Z. Khaliliullin, Z. Mi, C.-J. Li, *ACS Catal.* **2020**, *10*, 6248–6253; e) T. McCallum, S. P. Pitre, M. Morin, J. C. Scaiano, L. Barriault, *Chem. Sci.* **2017**, *8*, 7412–7418; f) J. Z. Wang, W. L. Lyon, D. W. C. MacMillan, *Nature* **2024**, *628*, 104–109.

[10] a) R. A. Garza-Sanchez, T. Patra, A. Tlahuext-Aca, F. Strieth-Kalthoff, F. Glorius, *Chem. Eur. J.* **2018**, *24*, 10064–10068; b) Z. Xie, P. Li, Y. Hu, N. Xu, L. Wang, *Org. Biomol. Chem.* **2017**, *15*, 4205–4211; c) S. Jiang, Z. Yang, Z. Guo, Y. Li, L. Chen, Z. Zhu, X. Chen, *Org. Biomol. Chem.* **2019**, *17*, 7416–7424.

[11] a) E. Mao, D. W. C. MacMillan, *J. Am. Chem. Soc.* **2023**, *145*, 2787–2793; b) E. J. McClain, A. K. Wortman, C. R. J. Stephenson, *Chem. Sci.* **2022**, *13*, 12158–12163; c) E. de Pedro Beato, D. Spinnato, W. Zhou, P. Melchiorre, *J. Am. Chem. Soc.* **2021**, *143*, 12304–12314; d) C. Jin, Z. Yan, B. Sun, J. Yang, *Org. Lett.* **2019**, *21*, 2064–2068; e) J. Genovino, Y. Lian, Y. Zhang, T. O.
Hope, A. Juneau, Y. Gagné, G. Ingle, M. Frenette, *Org. Lett.* **2018**, *20*, 3229-3232; f) X.-L. Lai, X.-M. Shu, J. Song, H.-C. Xu, *Angew. Chem. Int. Ed.* **2020**, *59*, 10626-10632; *Angew. Chem.* **2020**, *132*, 10713-10719; g) J. Z. Wang, E. Mao, J. A. Nguyen, W. L. Lyon, D. W. C. MacMillan, *J. Am. Chem. Soc.* **2024**, *146*, 15693-15700.

[12] A. Hu, J.-J. Guo, H. Pan, Z. Zuo, *Science* **2018**, *361*, 668-672.

[13] S. K. Kariofillis, B. J. Shields, M. A. Tekle-Smith, M. J. Zacuto, A. G. Doyle, *J. Am. Chem. Soc.* **2020**, *142*, 7683-7689.

[14] a) C. Le, Y. Liang, R. W. Evans, X. Li, D. W. C. MacMillan, *Nature* **2017**, *547*, 79-83; b) P. Zhang, C. C. Le, D. W. C. MacMillan, *J. Am. Chem. Soc.* **2016**, *138*, 8084-8087.

[15] F. Liu, Z.-P. Ye, Y.-Z. Hu, J. Gao, L. Zheng, K. Chen, H.-Y. Xiang, X.-Q. Chen, H. Yang, *J. Org. Chem.* **2021**, *86*, 11905-11914.

[16] a) W. Zhao, Y. Zhang, S. Yuan, X. Yu, L. Liu, J. Li, *J. Org. Chem.* **2023**, *88*, 6218-6226; b) G.-X. Li, C. A. Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu, G. Chen, *Chem. Sci.* **2016**, *7*, 6407-6412; c) C. Chen, M. Wang, H. Lu, B. Zhao, Z. Shi, *Angew. Chem. Int. Ed.* **2021**, *60*, 21756-21760; *Angew. Chem.* **2021**, *133*, 21924-21928; d) M. Abdellaoui, T. Dies, M.-A. Wiethoff, C. Bahri, G. Lemière, C. Ollivier, L. Fensterbank, *Adv. Synth. Catal.* **2023**, *365*, 884-891; e) Y. Sato, K. Nakamura, Y. Sumida, D. Hashizume, T. Hosoya, H. Ohmiya, *J. Am. Chem. Soc.* **2020**, *142*, 9938-9943.

[17] a) R. W. Pipal, K. T. Stout, P. Z. Musacchio, S. Ren, T. J. A. Graham, S. Verhoog, L. Gantert, G. Lohith, A. Schmitz, H. S. Lee, D. Hesk, E. D. Hostetler, I. W. Davies, D. W. C. MacMillan, *Nature* **2021**, *589*, 542-547; b) P. Natarajan, A. Basaka, O. Metin, *Green Chem.* **2023**, *25*, 3187-3197; c) X.-K. Qi, L.-J. Yao, M.-J. Zheng, L. Zhao, C. Yang, L. Guo, W. Xia, *ACS Catal.* **2024**, *14*, 1300-1310; d) M.-C. Wu, M.-Z. Li, Y.-X. Chen, F. Liu, J.-A. Xiao, K. Chen, H.-Y. Xiang, H. Yang, *Org. Lett.* **2022**, *24*, 6412-6416; e) L.-Z. Qin, M.-Y. Wu, X. Yuan, H. Sun, X. Duan, J.-K. Qiu, K. Guo, *Cell Rep. Phys. Sci.* **2024**, *5*, 101843.

[18] Selected references on fluoroalkyl sulfoximines used as fluoroalkyl radical sources in photochemical reactions, see: a) L. Barthelemy, E. Anselmi, T.-N. Le, G. Vo-Thanh, R. Guillot, K. Miqueu, E. Magnier, *J. Org. Chem.* **2019**, *84*, 4086-4094; b) S. Li, X. Wang, Y. Yang, C. Ni, J. Hu, *Org. Lett.* **2024**, *26*, 872-876; c) T. Duhail, S. Messaoudi, G. Dagousset, J. Marrot, C. André-Barrès, E. Magnier, E. Anselmi, *Adv. Synth. Catal.* **2023**, *365*, 2392-2399; d) J. Kalim, T. Duhail, T.-N. Le, N. Vanthuyne, E. Anselmi, A. Togni, E. Magnier, *Chem. Sci.* **2019**, *10*, 10516-10523; e) Y. Nakayama, G. Ando, M. Abe, T. Koike, M. Akita, *ACS Catal.* **2019**, *9*, 6555-6563; f) N. Noto, T. Koike, M. Akita, *ACS Catal.* **2019**, *9*, 4382-4387; g) M. Briand, L. D. Thai, F. Bourdreux, N. Vanthuyne, X. Moreau, E. Magnier, E. Anselmi, G. Dagousset, *Org. Lett.* **2022**, *24*, 9375-9380.

[19] For overviews on fluoroalkyl sulfoximines, see: a) V. Bizet, R. Kowalczyk, C. Bolm, *Chem. Soc. Rev.* **2014**, *43*, 2426-2438; b) X. Shen, J. Hu, *Eur. J. Org. Chem.* **2014**, 4437-4451; c) Y. Macé, E. Magnier, *Eur. J. Org. Chem.* **2012**, 2479-2494; d) A.-L. Barthelemy, E. Magnier, C. R. Chim. **2018**, *21*, 711-722; e) X. Wang, J. Hu, *Phosphorus Sulfur Silicon Relat. Elem.* **2024**, *199*, 10-22; f) T. Koike, *Chem. Rec.* **2023**, *23*, e202300032.

[20] T. Duhail, M. Zhu, C. Rombault, G. Dagousset, S. Messaoudi, E. Magnier, E. Anselmi, *Eur. J. Org. Chem.* **2022**, e202200173.

[21] P. Wu, J. S. Ward, K. Rissanen, C. Bolm, *Adv. Synth. Catal.* **2023**, *365*, 522-526.

[22] Deposition numbers 2337839 for 2a contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.

[23] For inspiring work on this H/D-exchange reaction, see: J. Scheigetz, C. Berthelette, C. Li, R. J. Zamboni, *J. Labelled Compd. Radiopharm.* **2004**, *47*, 881-889.

[24] Selected references on the use of fluorinated N-Ts sulfoximines as fluoroalkyl sources, see: a) X. Shen, M. Zhou, C. Ni, W. Zhang, J. Hu, *Chem. Sci.* **2014**, *5*, 117-122; b) M. Daniel, G. Dagousset, P. Diter, P.-A. Klein, B. Tuccio, A.-M. Goncalves, G. Masson, E. Magnier, *Angew. Chem. Int. Ed.* **2017**, *56*, 3997-4001; *Angew. Chem.* **2017**, *129*, 4055-4059; c) W. Zhang, F. Wang, J. Hu, *Org. Lett.* **2009**, *11*, 2109-2112; d) E. Selmi-Higashi, J. Zhang, X. C. Cambeiro, S. Arseniyadis, *Org. Lett.* **2021**, *23*, 4239-4243; e) Z.-S. Wang, Y.-B. Chen, H.-W. Zhang, Z. Sun, C. Zhu, L.-W. Ye, *J. Am. Chem. Soc.* **2020**, *142*, 3636-3644; f) N. Noto, K. Takahashi, S. Goryo, A. Takakado, K. Iwata, T. Koike, M. Akita, *J. Org. Chem.* **2020**, *85*, 13220-13227; g) R. Taniguchi, N. Noto, S. Tanaka, K. Takahashi, S. K. Sarkar, R. Oyama, M. Abe, T. Koike, M. Akita, *Chem. Commun.* **2021**, *57*, 2609-2612.

[25] For a few low-boiling olefins, the corresponding products were observed in the crude ¹H NMR spectra, but they could not be isolated (for further details, see the Supporting Information).

[26] a) B. Gao, S. Li, P. Wu, J. E. Moses, K. B. Sharpless, *Angew. Chem. Int. Ed.* **2018**, *57*, 1939-1943; *Angew. Chem.* **2018**, *130*, 1957-1961; b) S. Teng, Z. P. Shultz, C. Shan, L. Wojtas, J. M. Lopchuk, *Nat. Chem.* **2024**, *16*, 183-192.

[27] https://tools.niehs.nih.gov/stdb/index.cfm.

[28] X. Wang, M. Frings, K. Rissanen, C. Bolm, *J. Org. Chem.* **2023**, *88*, 2666-2669.

[29] G. Y. Cho, C. Bolm, *Org. Lett.* **2005**, *7*, 1351-1354.

[30] F. Lemasson, H.-J. Gais, J. Runsink, G. Raabe, *Eur. J. Org. Chem.* **2010**, 2157-2175.

[31] D. Craig, N. J. Geach, C. J. Pearson, A. M. Z. Slawin, A. J. P. White, D. J. Williams, *Tetrahedron* **1995**, *51*, 6071-6098.

[32] a) N. Luo, Z. Zhan, Z. Ban, G. Lu, J. He, F. Hu, G. Huang, *Adv. Synth. Catal.* **2020**, *362*, 3126-3130; b) R. Sun, X. Yang, X. Chen, C. Zhang, X. Zhao, X. Wang, X. Zheng, M. Yuan, H. Fu, R. Li, H. Chen, *Org. Lett.* **2018**, *20*, 6755-6759.

[33] C. Zhou, M. Huang, Y. Yao, C. Chen, X. Yi, K.-f. Yang, G.-Q. Lai, W. Xuan, P. Zhang, *Org. Biomol. Chem.* **2023**, *21*, 9534-9541.

[34] F. Scheidt, J. Neufeld, M. Schäfer, C. Thiehoff, R. Gilmour, *Org. Lett.* **2018**, *20*, 8073-8076.

[35] a) B. Zhang, C. Mück-Lichtenfeld, C. G. Daniliuc, A. Studer, *Angew. Chem. Int. Ed.* **2013**, *52*, 10792-10795; *Angew. Chem.* **2013**, *125*, 10992-10995; b) J.-X. Yu, Y.-Y. Cheng, B. Chen, C.-H. Tung, L.-Z. Wu, *Angew. Chem. Int. Ed.* **2022**, *61*, e202209293; *Angew. Chem.* **2022**, *134*, e202209293.

[36] a) A. A. Reddy, K. R. Prasad, *J. Org. Chem.* **2017**, *82*, 13488-13499; b) J. Miguélez, A. Boto, R. Marín, M. Díaz, *Eur. J. Med. Chem.* **2013**, *66*, 540-554.

[37] W. Kong, E. Merino, C. Nevado, *Angew. Chem. Int. Ed.* **2014**, *53*, 5078-5082; *Angew. Chem.* **2014**, *126*, 5178-5182.

[38] a) C. B. Tripathi, S. Mukherjee, *Angew. Chem. Int. Ed.* **2013**, *52*, 8450-8453; *Angew. Chem.* **2013**, *125*, 8608-8611; b) X.-T. Li, Q.-S. Gu, X.-Y. Dong, X. Meng, X.-Y. Liu, *Angew. Chem. Int. Ed.* **2018**, *57*, 7668-7672; *Angew. Chem.* **2018**, *130*, 7794-7798.

[39] a) Y. Zhang, B. Yu, B. Gao, T. Zhang, H. Huang, *Org. Lett.* **2019**, *21*, 535-539; b) H.-M. Huang, P. Bellotti, C. G. Daniliuc, F. Glorius, *Angew. Chem. Int. Ed.* **2021**, *60*, 2464-2471; *Angew. Chem.* **2021**, *133*, 2494-2501.

[40] a) T. Wu, X. Mu, G. Liu, *Angew. Chem. Int. Ed.* **2011**, *50*, 12578-12581; *Angew. Chem.* **2011**, *123*, 12786-12789; b) Y.-L. Li, J.-B. Wang, X.-L. Wang, Y. Cao, J. Deng, *Eur. J. Org. Chem.* **2017**, 6052-6059; c) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian, S.-D. Yang, *Angew. Chem. Int. Ed.* **2013**, *52*, 3972-3976; *Angew. Chem.* **2013**, *125*, 4064-4068; d) X. Li, H. Zhao, L.
Meng, J. Dong, C. Yang, Z. Wei, X. Wang, J. Xu, B. Fan, *J. Org. Chem.* **2023**, *88*, 5300–5310.

[41] J. Xu, H. Yang, L. He, L. Huang, J. Shen, W. Li, P. Zhang, *Org. Lett.* **2021**, *23*, 195–201.

[42] a) J. Guo, C. Kuang, J. Rong, L. Li, C. Ni, J. Hu, *Chem. Eur. J.* **2019**, *25*, 7259–7264; b) R. Kowalczyk, A. J. F. Edmunds, R. G. Hall, C. Bolm, *Org. Lett.* **2011**, *13*, 768–771.

[43] G.-f. Yang, Y. Yuan, Y. Tian, S.-q. Zhang, X. Cui, B. Xia, G.-x. Li, Z. Tang, *J. Am. Chem. Soc.* **2023**, *145*, 5439–5446.

[44] D. R. Duling, *J. Magn. Reson. 1994*, *Series B* **104**, 105–110.

[45] Y. Wang, L. Zhang, Y. Yang, P. Zhang, Z. Du, C. Wang, *J. Am. Chem. Soc.* **2013**, *135*, 18048–18051.

[46] V. Balakrishnan, V. Murugesan, B. Chindan, R. Rasappan, *Org. Lett.* **2021**, *23*, 1333–1338.

[47] W. Luo, L.-M. Zhang, Z.-M. Zhang, J. Zhang, *Angew. Chem. Int. Ed.* **2022**, *61*, e202204443; *Angew. Chem.* **2022**, *134*, e202204443.

[48] C. Bo, F. Chen, Q. Bu, Z.-H. Du, M. Li, B. Dai, N. Liu, *J. Org. Chem.* **2023**, *88*, 3532–3538.

[49] D. Heijnen, H. Helbert, G. Luurtsema, P. H. Elsinga, B. L. Feringa, *Org. Lett.* **2019**, *21*, 4087–4091.

[50] Q. Dai, J. Yu, Y. Jiang, S. Guo, H. Yang, J. Cheng, *Chem. Commun.* **2014**, *50*, 3865–3867.

[51] M. de Robichon, T. Kratz, F. Beyer, J. Zuber, C. Merten, T. Bach, *J. Am. Chem. Soc.* **2023**, *145*, 24466–24470.

[52] X. Liu, Z. Guo, Y. Liu, X. Chen, J. Li, D. Zou, Y. Wu, Y. Wu, *Org. Biomol. Chem.* **2022**, *20*, 1391–1395.

[53] A. Sandvoß, J. M. Wahl, *Org. Lett.* **2023**, *25*, 5795–5799.

[54] L. Zhang, S. Chen, H. He, W. Li, C. Zhu, J. Xie, *Chem. Commun.* **2021**, *57*, 9064–9067.

[55] T.-J. Y. W. Hu, H. Peng, J. Cheng, *Tetrahedron Lett.* **2016**, *57*, 4109–4112.

[56] P. Natarajan, A. Basaka, O. Metin, *Green Chem.* **2023**, *25*, 3187–3197.

Manuscript received: July 2, 2024

Accepted manuscript online: September 5, 2024

Version of record online: October 31, 2024