# Pseudo-4-component photoredox-catalyzed alkylative amidination/carbamoylation of styrenes with isocyanides and redox-active esters

Alexandre Simon, Virgile Rouffeteau, Camilla Acconcia, Sylvestre P J T

Bachollet, Jérémy Forté, Mariateresa Giustiniano, Laurence Grimaud,
Maxime R Vitale

► To cite this version:

Alexandre Simon, Virgile Rouffeteau, Camilla Acconcia, Sylvestre P J T Bachollet, Jérémy Forté, et al.. Pseudo-4-component photoredox-catalyzed alkylative amidination/carbamoylation of styrenes with isocyanides and redox-active esters. Organic Chemistry Frontiers, 2025, 12 (12), pp.3551-3557. 10.1039/D5QO00352K . hal-05118052

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Submitted on 18 Jun 2025

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# Pseudo-4-Component Photoredox-catalyzed Alkylative Amidination / Carbamoylation of Styrenes with Isocyanides and Redox-Active Esters

Alexandre Simon,ª Virgile Rouffeteau,ª Camilla Acconcia,ª Sylvestre P. J. T. Bachollet,ª Jérémy Forté,ᵇ Mariateresa Giustiniano,ᶜ Laurence Grimaudª* and Maxime R. Vitaleª*

We report a photoredox-catalyzed pseudo-four-component process for the alkylative amidation of styrenes using isocyanides and redox-active esters (RAEs). This redox-neutral radical-polar crossover reaction shows broad functional group tolerance. The RAE serves as both a radical and nucleophile source, with the initially released phthalimide anion reintegrated into the final product. The resulting amidines can be readily derivatized into amides, tetrazoles, nitriles, or aldehydes, enhancing the synthetic utility of this approach

## Introduction

Multicomponent reactions (MCRs) are invaluable tools for the eco-efficient and straightforward synthesis of complex molecules from readily available building blocks.¹⁻⁹ In this domain, the 1,2-difunctionalization of alkenes serves as a prime example.¹⁰⁻³⁰ In spite of the considerable progresses achieved to date, this area continues to attract significant interest. Initially confined to palladium- and, more recently, nickel-catalyzed processes,¹⁰⁻¹⁴ this field experienced a significant breakthrough with Akita's pioneering development of the photoredox-catalyzed oxytrifluoromethylation of styrenes.¹⁵ By means of radical-polar crossover reaction mechanisms,³¹⁻³³ photoredox catalysis has paved the way for a diverse array of multicomponent difunctionalizations of alkenes.¹⁵⁻²⁹ Advancements in this field have notably been achieved by modifying the radical precursor and/or the nucleophile or electrophile involved in the polar coupling event (Scheme 1, eq. (a)). However, most of these MCRs remain limited to the coupling of only three components, with examples involving four or more components being scarcer.²²⁻²⁸

In this context, we envisioned to use isocyanides in radical-cationic photoredox-catalyzed processes.²⁹ These reagents, with a long-standing history in MCRs,⁷⁻⁹ present the advantage of being ambiphilic, enabling them to react first as nucleophiles and then, as electrophiles.³⁴ In principle, this combination could potentially enable a 4-component photoredox-catalyzed process. Nevertheless, to the best of our knowledge, the use of isocyanides in alkene difunctionalization reactions has been reported only once, in a study by Gevorgyan's group. The authors demonstrated that, under blue light irradiation, a palladium(0)/Xantphos catalytic system enables the three-component coupling of primary or secondary alkyl iodides, styrene derivatives, and isocyanides.³⁰ The authors demonstrated that, under blue light irradiation, a palladium(0)/Xantphos catalytic system enables the three-component coupling of primary or secondary alkyl iodides, styrene derivatives, and isocyanides.

<figure><img src="image_2.png" /><figcaption>(b) Three-component difunctionalization of alkenes with isocyanides³⁰</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>(c) Four-component difunctionalization of alkenes with isocyanides</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>(d) This work</figcaption></figure>

<figure><img src="image_5.png" /></figure>

**Scheme 1** Context and aim of this work

This process, which does not strictly follow a radical-polar crossover pathway, leads to the in situ formation of ketenimines, which subsequently undergo hydrolysis to afford the corresponding amides or, upon Lewis acid-promoted fragmentation, yield the corresponding nitriles (Scheme 1, eq. (b)).³⁰ Notably, this study requires a high catalyst loading, and its scope is limited to primary and secondary alkyl iodides, with no reported examples involving tertiary alkyl iodides.

The four-component functionalization of alkenes with isocyanides presents significant challenges. After generating the desired carbocation, it must first be trapped by the isocyanide to form the corresponding nitrilium ion, which is then intercepted by a second nucleophile present in the reaction
mixture (Scheme 1, eq. (c) – path A). However, this second nucleophile can also directly react with the transient carbocation, resulting in the competitive formation of an undesired three-component adduct (Scheme 1, eq. (c) – path B). To address this issue, following the strategy employed by Akita et al. in the context of the intermolecular aminotrifluoromethylation of alkenes,²² using a very large excess of isocyanide could favor the predominant trapping of the carbocation. However, using isocyanide as a (co)-solvent is impractical and conflicts with principles of green and sustainable chemistry. To address this problem, we propose an alternative strategy where the radical precursor also acts as the primary nucleophile source. The key advantage of this approach is that the typically low amounts of photocatalyst ensure minimal concentrations of both the carbocation and the second nucleophile. As a result, the isocyanide maintains a relatively high effective concentration throughout the reaction, promoting its preferential trapping of the carbocation. Building on this idea, we report that, starting from N-hydroxyphthalimide-derived Redox-Active Esters (RAEs), the redox-neutral pseudo-4-component alkylative amidination or carbamoylation of styrenes with isocyanides can be achieved (Scheme 1, eq. (d)).

## Results and discussion

At the onset of this work, we decided to test the feasibility of our approach by studying the model multicomponent reaction of the adamantane-derived RAE **1a**, with styrene **2a** and *tert*-butyl-isocyanide **3a**. Inspired from literature precedents,³⁵⁻³⁸ Ir(ppy)₃ was initially selected as photocatalyst because its oxidation potential at the excited state (E<sub>ox</sub>(Ir(ppy)₃)* = -1.73V) is sufficiently low to promote the reduction of RAEs (E<sub>red</sub>(RAE) ~ -1.2 V).³⁹ The reactions were irradiated with a 405 nm blue LED lamp under argon atmosphere for 24 hours.⁴⁰

A preliminary test reaction employing 1.0 equivalent of **1a**, 4.0 equivalents of **2a**, and 5.0 equivalents of **3a** successfully yielded the desired product. Under these conditions, the target pseudo four-component adduct, **4a**, was obtained with an encouraging 50% NMR yield, along with a minor by-product, the amide derivative **5a** (2% NMR yield) (Table 1, entry 1).

<table><caption>**Table 1** optimization table</caption><thead><tr><th>entry</th><th>deviation from above</th><th>yields (%)<sup>a</sup><br>4a / 5a</th></tr></thead><tbody><tr><td>1<sup>b</sup></td><td>none</td><td>50 / 2</td></tr><tr><td>2</td><td>N-phenyl-(benzo)phenothiazine<br>(10 mol%)<sup>c</sup></td><td>24 / 0</td></tr><tr><td>3</td><td>+ CuCl (1 mol%)</td><td>37 / 2</td></tr></tbody></table>

<table><tbody><tr><td>4</td><td>+ CuBr (1 mol%)</td><td>46 / 2</td></tr><tr><td>5</td><td>+ CuI (1 mol%)</td><td>40 / 4</td></tr><tr><td>6</td><td>+ Cu(MeCN)<sub>4</sub>BF<sub>4</sub> (1 mol%)</td><td>59 / 2</td></tr><tr><td>7<sup>d</sup></td><td>2a (2.0 eq)</td><td>39 / 3</td></tr><tr><td>8<sup>d</sup></td><td>2a (2.0 eq), 3a (2.5 eq)</td><td>43 / 4</td></tr><tr><td>9<sup>d</sup></td><td>1a (1 eq, 1.0 M), 2a (2.0 eq),<br>3a (2.5 eq) in DCM: MeCN 1:1</td><td>55 (55)<sup>e</sup> / 4</td></tr><tr><td>10<sup>d</sup></td><td>no photocatalyst</td><td>-<sup>f</sup></td></tr><tr><td>11<sup>d</sup></td><td>no light</td><td>-<sup>f</sup></td></tr><tr><td>12<sup>d</sup></td><td>under air</td><td>44 / 8</td></tr></tbody></table>

a determined by ¹H NMR analysis of the crude reaction mixture using 1,1-diphenylethylene as external reference. b reaction conditions: RAE **1a** (0.20 mmol, 1.0 eq, 0.5 M in dry acetonitrile), styrene **2a** (4.0 eq), and *tert*-butyl isocyanide **3a** (5.0 eq) in a EvoluChem PhotoRedOx BoxTM in the presence of Ir(ppy)₃ (0.5 mol%) as the photocatalyst. The reaction was irradiated with EvoluChem 18W blue LEDs (405 nm) for 24h, under inert argon atmosphere (1 atm). c instead of Ir(ppy)₃. d Cu(MeCN)<sub>4</sub>BF<sub>4</sub> (1 mol%) was added. e isolated yield. f no reaction.

Given its recent applications in the reduction of RAEs,⁴¹,⁴² the organic photoredox catalyst N-phenyl-(benzo)phenothiazine was also evaluated. However, in this case, **4a** was formed in a lower yield, despite using a significantly higher catalyst loading (Table 1, entry 2). Inspired by the alkylative cyanation of styrene,³⁵ we next explored the use of copper(I)-based additives to improve the reaction.⁴³ While 1 mol% of CuCl, CuBr, or CuI notably reduced the reaction yield, the use of cationic tetrakis(acetonitrile)copper(I) tetrafluoroborate led to an approximately 20% relative increase in yield (from 50% to ~59%, Table 1, entry 6 vs entry 1). The use of this additive was thus kept for the rest of our study.

To improve the environmental sustainability of this reaction, we aimed to reduce the quantities of styrene and isocyanide required. Using 2.0 equivalents of **2a** with either 5.0 or 2.5 equivalents of **3a** led to a significant drop in reaction yield (Table 1, entries 7–8). To overcome this issue, we increased the concentration of **1a** from 0.5 M to 1 M. However, solubility problems arose when pure acetonitrile was used, necessitating a dichloromethane (DCM)/acetonitrile (1:1) solvent mixture instead. Under these conditions, 2.0 equivalents of **2a** and 2.5 equivalents of **3a** enabled the formation of the MCR amidine adduct **4a** with a reasonable 55% NMR yield (55% isolated yield), accompanied by 4% of the carbamoylated by-product **5a** (Table 1, Entry 9).

Control experiments conducted in the absence of either the photocatalyst or the light source did not yield the desired product (Table 1, entries 10–11), confirming that the reaction relies on a photoredox-catalyzed mechanism. Additionally, performing the reaction under ambient atmospheric conditions resulted in a reduced yield of **4a** and an increased formation of the by-product **5a**, possibly due to the hydrolysis of the former into the latter or the trapping of the nitrilium intermediate by residual water.

Notably, the structure of **4a** was later confirmed by analogy to that of compound **4b**. The latter was obtained in 67% yield by reacting the pivalic acid-derived RAE **1b** with **2a** and **3a**, and its structure was validated through X-ray diffraction analysis of a single crystal (Scheme 2).⁰
<figure><img src="image_6.png" /><figcaption>**Scheme 2** Synthesis and X-Ray analysis of 4b</figcaption></figure>

With the optimized reaction conditions established, we next explored the scope of this pseudo-four-component photoredox-catalyzed process. To do so, several other RAEs (1c-k) were synthesized and tested in reactions with styrene 2a and tert-butyl isocyanide 3a. However, due to the frequent occurrence of mixtures of MCR adducts 4 and the corresponding amide 5 during purification, we opted to perform a quantitative hydrolysis of the crude reaction mixtures before the purification step. Consequently, the yields of the carbamoyl derivatives 5 reflect the overall efficiency of the pseudo-four-component reaction leading to the amidine derivatives 4 (Scheme 3).

Tertiary aliphatic and cyclic RAEs 1c-e, derived from methyl cyclohexane carboxylic acid, methyl cyclopentane carboxylic acid, and methyl cyclopropane carboxylic acid, respectively, were initially evaluated. Satisfactory yields of 60% and 63% were obtained with 1c and 1d. In contrast, the cyclopropyl derivative 5e was produced in only 17% yield, likely due to the poor stability of the intermediate tertiary cyclopropyl radical.

<figure><img src="image_7.png" /><figcaption>**Scheme 3** Scope of the reaction with different RAEs</figcaption></figure>

The six-membered heterocyclic RAEs 1f and 1g also performed well, affording the corresponding tetrahydropyran 5f and N-Boc piperidine 5g in 66% and 47% yields, respectively. However, the cyclohexane carboxylic acid-derived RAE 1h, which generates a transient secondary alkyl radical, significantly reduced reaction efficiency, yielding only 21% of 5h. Non-cyclic tertiary RAEs, such as the allylic and acetoxy derivatives 1i and 1j, were also compatible with this reaction, but the corresponding carbamoylated products 5i and 5j were obtained in lower yields. When using the 2-phenylacetic acid-derived RAE 1k, we observed complete conversion of the starting material but no formation of the MCR adduct 5k. We propose that, in this case, the transient benzylic radical is oxidized by PC⁺ before it can add to styrene, thus disrupting the intended radical-polar reaction cascade.

We next investigated the reaction's scope using a range of styrenes (2b-l, Scheme 4).

Alkyl-substituted styrenes, including 4-Me-, 3-Me-, 2-Me-, and 4-`Bu-substituted variants, showed good performance in this reaction. The best yield, 80%, was obtained with the 4-Me-substituted styrene, yielding the desired carbamoylated product 7a. Steric hindrance had minimal impact on reaction efficiency, as the 2-Me-substituted product 7c was isolated in a 67% yield, identical to that of unsubstituted styrene (5b).

Other electron-rich styrenes, such as those substituted with a methoxy or acetoxy group at the 4-position, were also suitable for this reaction, producing the corresponding products 7e and 7f in 46% and 67% yields, respectively. Similarly, styrenes bearing a halogen atom at the 3- or 4-position were viable substrates, though lower yields (37-52%) were observed. Notably, using a styrene with an extended π-system, such as 2-vinylnaphthalene, produced the desired amide 7k with a satisfactory yield of 79%.
<figure><img src="image_8.png" /><figcaption>**Scheme 4** Scope of the reaction with different styrenes</figcaption></figure>

The reaction scope with various isocyanides (3b-j) was subsequently evaluated using the pivalic acid derived RAE 1b and the 4-acetoxy styrene 2g. In this case, the pseudo-four-component amidine adducts **8** exhibited greater stability toward hydrolysis and were directly isolated at the end of the MCR process (Scheme 5).

Replacing *tert*-butyl isocyanide with other aliphatic isocyanides, such as cyclohexyl isocyanide (3b), cyclopentyl isocyanide (3c), or *n*-pentyl isocyanide (3d), did not affect the reaction. The corresponding amidines **8a**, **8b**, and **8c** were isolated in good yields ranging from 51% to 55%.

Next, several benzylic isocyanides were tested. Benzyl isocyanide (3e), 4-bromo benzyl isocyanide (3f), and the 4-piperonylamine-derived isocyanide (3g) were compatible with this pseudo-four-component reaction, though the corresponding MCR adducts **8d**, **8e**, and **8f** were obtained in slightly lower yields. The tertiary dimethyl-substituted benzylic isocyanide **3h**, likely more nucleophilic than benzyl isocyanide, performed better, producing the amidine compound **8g** in 68% yield. In contrast, the use of aryl isocyanides **3i** and **3j** did not yield the desired MCR adducts **8h** and **8i**. Instead, poor

conversion of the starting RAE **1b** was observed, suggesting that aryl isocyanides may have an inhibitory effect on the reaction.

<figure><img src="image_9.png" /><figcaption>**Scheme 5** Scope of the reaction with different isocyanides</figcaption></figure>

To further demonstrate the versatility of this method, we conducted a scale-up experiment using 2.0 mmol of **1b** (instead of 0.2 mmol), in combination with styrene **2a** and *tert*-butyl isocyanide **3a**. Notably, the desired amidine derivative **4b** was obtained in 71% yield, comparable to the 67% yield observed on a smaller scale. With this amidine product in hand, we then explored its potential as a platform for various derivatization reactions (Scheme 6).

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

Reaction conditions: (a) $SiO_2$, $CH_2Cl_2$, rt, 24h-48h. (b) $TMSN_3$ (2.0 eq), MeOH (5.0 eq), $Sc(OTf)_3$ (10 mol%), $CH_2Cl_2$, rt, o/n. (c) HFIP, 60°C, 24h. (d) DIBAL-H (2.0 eq), $Et_2O$, rt, then AcOH(aq).
As previously discussed, **4b** underwent quantitative hydrolysis upon reaction with silica in dichloromethane, yielding **5b**. Treatment with trimethylsilyl azide (2.0 eq) and a catalytic amount of scandium triflate (10 mol%) in the presence of methanol (5.0 eq) afforded tetrazole **9** in 94% yield. Refluxing **4b** in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) induced fragmentation of the *tert*-butyl group, leading to the formation of nitrile **10** in an excellent 96% yield. Finally, reduction with diisobutylaluminium hydride (2.0 eq) in diethyl ether, followed by acidic hydrolysis, provided aldehyde **11** in 51% yield.

Based on literature precedents, we propose that the reaction proceeds via the mechanistic pathway outlined in Scheme 7.

<figure><img src="image_11.png" /><figcaption>**Scheme 7** Mechanistic proposal</figcaption></figure>

Initially, as previously demonstrated by others,³⁵⁻³⁹ photoexcited Ir(ppy)₃* reduces the RAE **1**, generating the alkyl radical **A**, which subsequently adds to styrene **2**, forming the secondary benzyl radical **B**. This intermediate is then oxidized to the carbocation **C**, either by the Cu(II) complex formed when Ir(ppy)₃* is reduced by Cu(I) (path a) or directly by Ir(ppy)₃* itself (path b). Nucleophilic addition of the isocyanide then leads to the nitrilium ion **D**, which is ultimately captured by the initially released phthalimide anion, yielding the pseudo-4-component adduct **4**. In support of this mechanistic proposal, we conducted several experiments, which notably confirmed the crucial role of light irradiation (on-off experiment). Additionally, the TEMPO-mediated radical trapping and competitive quenching with water further validated the formation of intermediates **A**–**D** (see ESI for more information).

## Conclusions

In conclusion, we have developed a photoredox-catalyzed process enabling the alkylative amidination or carbamoylation of styrenes using isocyanides and redox-active esters. This radical-polar crossover reaction exhibits good functional group tolerance and a reasonable substrate scope. A key aspect of this method is the dual role of the redox-active ester as both a radical and nucleophile source. The initially released phthalimide anion is ultimately reintegrated into the final product by trapping a transient nitrilium ion, enabling a pseudo-

4-component process. The resulting amidine products can be readily derivatized into amides, tetrazoles, nitriles, or aldehydes, further expanding the utility of this approach. Ongoing studies focused on extending this strategy to other radical sources capable of acting as nucleophiles will be reported in due course.

## Author contributions

A.S. carried out most of the experimental work in this study. V.R. conducted complementary experiments for the manuscript. C.A. & S.P.J.T. contributed to the preparation of various substrates. J.F. carried out the X-ray analysis. M.G. participated to the project design. L.G. and M.R.V. designed the project and supervised it. M.R.V. wrote the manuscript.

## Conflicts of interest

There are no conflicts to declare.

## Acknowledgements

The authors gratefully thank the Agence Nationale de la Recherche (ANR-20-CE07-0020, ELMER), the CNRS, the ENS and Sorbonne University for financial support. The authors thank the Università Italo-Francese, the “Institut Francais” of the French embassy in Italie and Campus France for supporting the Galileo Project (G24-227, 50454WC).

## References

1. Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; WileyVCH: Weinheim, Germany, **2005**.

2. R. C. Cioc, E. Ruijter and R. V. A. Orru, Multicomponent reactions: advanced tools for sustainable organic synthesis, *Green Chem.*, 2014, **16**, 2958–2975.

3. A. Dömling, W. Wang and K. Wang, Chemistry and Biology Of Multicomponent Reactions, *Chem. Rev.*, 2012, **112**, 3083–3135.

4. J. E. Biggs-Houck, A. Younai and J. T. Shaw, Recent advances in multicomponent reactions for diversity-oriented synthesis, *Curr. Opin. Chem. Biol.*, 2010, **14**, 371–382.

5. E. Ruijter and R. V. A. Orru, Multicomponent reactions – opportunities for the pharmaceutical industry, *Drug Discov. Today Technol.*, 2013, **10**, e15–e20.

6. B. B. Touré and D. G. Hall, Natural Product Synthesis Using Multicomponent Reaction Strategies, *Chem. Rev.*, 2009, **109**, 4439–4486.

7. Dömling and I. Ugi, Multicomponent Reactions with Isocyanides, *Angew. Chem. Int Ed.*, 2000, **39**, 3168–3210.

8. A. Dömling, Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry, *Chem. Rev.*, 2006, **106**, 17–89.

9. M.Giustiniano, L. Moni, L. Sangaletti, S. Pelliccia, A. Basso, E. Novellino and G. Tron, Interrupted Ugi and Passerini Reactions: An Underexplored Treasure Island, *Synthesis*, 2018, **50**, 3549–3570.

10. S. Zhu, X. Zhao, H. Li and L. Chu, Catalytic three-component dicarbofunctionalization reactions involving radical capture by nickel, *Chem. Soc. Rev.*, 2021, **50**, 10836–10856.

11. J. Derosa, O. Apolinar, T. Kang, V. T. Tran and K. M. Engle, Recent developments in nickel-catalyzed intermolecular
dicarbofunctionalization of alkenes, *Chem. Sci.*, 2020, **11**, 4287-4296.

12 X. Qi and T. Diao, Nickel-Catalyzed Dicarbofunctionalization of Alkenes, *ACS Catal.*, 2020, **10**, 8542-8556.

13 R. K. Dhungana, S. KC, P. Basnet and R. Giri, Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins, *Chem. Rec.*, 2018, **18**, 1314-1340.

14 J. Zhang, L. Liu, T. Chen and L. Han, Transition-Metal-Catalyzed Three-Component Difunctionalizations of Alkenes, *Chem. Asian J.*, 2018, **13**, 2277-2291.

15 Y. Yasu, T. Koike and M. Akita, Three-component Oxytrifluoromethylation of Alkenes: Highly Efficient and Regioselective Difunctionalization of C=C Bonds Mediated by Photoredox Catalysts, *Angew. Chem. Int. Ed.*, 2012, **51**, 9567-9571.

16 S. Garbarino, D. Ravelli, S. Protti and A. Basso, Photoinduced Multicomponent Reactions, *Angew. Chem. Int. Ed.*, 2016, **55**, 15476-15484.

17 P. Yadav, A. Anagha Varma, A. J. Punnya and P. Gopinath, Photoredox-mediated Multicomponent Reactions, *Asian J. Org. Chem.*, 2022, **11**, e202200390.

18 G. A. Coppola, S. Pillitteri, E. V. Van der Eycken, S.-L. You and U. K. Sharma, Multicomponent reactions and photo/electrochemistry join forces: atom economy meets energy efficiency, *Chem. Soc. Rev.*, 2022, **51**, 2313-2382.

19 S. Ariya, M. Neetha and G. Anilkumar, Photocatalytic Multi-Component Reactions: An Emerging Avenue, *Curr. Catal.*, 2023, **1**, 1-17.

20 Y. Liu, H. Liu, X. Liu and Z. Chen, Recent Advances in Photoredox-Catalyzed Difunctionalization of Alkenes, *Catalysts*, 2023, **13**, 1056.

21 L. Pantaine, C. Bour, G. Masson, Photo-Induced Multi-Component Reactions. In *Photochemistry: Volume 46*; A. Albini, S. Protti, Eds.; The Royal Society of Chemistry, 2018; **Vol. 46**, pp 395-431.

22 Y. Yasu, T. Koike and M. Akita, Intermolecular Aminotrifluoromethylation of Alkenes by Visible-Light-Driven Photoredox Catalysis, *Org. Lett.*, 2013, **15**, 2136-2139.

23 G. Levitre, G. Dagousset, E. Anselmi, B. Tuccio, E. Magnier and G. Masson, Four-Component Photoredox-Mediated Azidoalkoxy-trifluoromethylation of Alkenes, *Org. Lett.*, 2019, **21**, 6005-6010.

24 X. Zhou, G. Li, Z. Shao, K. Fang, H. Gao, Y. Li and Y. She, Four-component acyloxy-trifluoromethylation of arylalkenes mediated by a photoredox catalyst, *Org. Biomol. Chem.*, 2019, **17**, 24-29.

25 L. M. Kammer, M. Krumb, B. Spitzbarth, B. Lipp, J. Kühlborn, J. Busold, O. M. Mulina, A. O. Terentev and T. Opatz, Photoredox-Catalyzed Four-Component Reaction for the Synthesis of Complex Secondary Amines, *Org. Lett.*, 2020, **22**, 3318-3322.

26 Y. Lv, J. Luo, M. Lin, H. Yue, B. Dai and L. He, A visible-light photoredox-catalyzed four-component reaction for the construction of sulfone-containing quinoxalin-2(1H)-ones, *Org. Chem. Front.*, 2021, **8**, 5403-5409.

27 H. Ma, Y. Li, P. Wang, J. Ye, J. Zhang, G. Liu and J. Wu, Photoredox-catalyzed intermolecular azidosulfonylation of alkenes with DABCO-(SO₂)₂, trimethylsilyl azide and thianthrenium salts, *Org. Chem. Front.*, 2023, **10**, 866-871.

28 L. Y. Vázquez-Amaya, B. Dootselaere, G. M. Ojeda-Carralero, S. Pillitteri, J. Van der Eycken, E. V. Van der Eycken and U. K. Sharma, Light-Driven Four-Component Reaction with Boronic Acid Derivatives as Alkylating Agents: An Amine/Imine-Mediated Activation Approach, *Org. Lett.*, 2023, **25**, 4010-4015.

29 C. Russo, F. Brunelli, G. Cesare Tron and M. Giustiniano, Isocyanide-Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis, *Chem. Eur. J.*, 2023, **29**, e202203150.

30 X. Jia, Z. Zhang and V. Gevorgyan, Three-Component Visible-Light-Induced Palladium-Catalyzed 1,2-Alkyl Carbamoylation/Cyanation of Alkenes, *ACS Catal.*, 2021, **11**, 13217-13222.

31 Reactions of arenediazonium salts with tetrathiafulvalene and related electron donors: A study of "radical-polar crossover" reactions. N. Bashir, B. Patro, J. A. Murphy, in *Advances in Free Radical Chemistry* Vol. 2, Ed. S. Z. Zard, JAI Press, USA, 1999, pp. 123-150.

32 J. A. Murphy, Free radicals in synthesis. Clean reagents affording oxidative or reductive termination, *Pure Appl. Chem.*, 2000, **72**, 1327-1334.

33 The Radical-Polar Crossover Reaction. J. A. Murphy, in *Radicals in Organic Synthesis*, Eds. P. Renaud, M. P. Sibi, Wiley, 2001, pp. 298-315.

34 *Isocyanide Chemistry*, Ed. G. Nenajdenko, Wiley, 2012.

35 W. Sha, L. Deng, S. Ni, H. Mei, J. Han and Y. Pan, Merging Photoredox and Copper Catalysis: Enantioselective Radical Cyanoalkylation of Styrenes, *ACS Catal.*, 2018, **8**, 7489-7494.

36 X. Wang, Y.-F. Han, X.-H. Ouyang, R.-J. Song and J.-H. Li, The photoredox alkylarylation of styrenes with alkyl N-hydroxyphthalimide esters and arenes involving C-H functionalization, *Chem. Commun.*, 2019, **55**, 14637-14640.

37 J. Yu, L. Zhu, X. Hong, H. Gao and T. Chen, Visible light-induced alkylpyridylation of styrenes via a reductive radical three-component coupling, *Org. Biomol. Chem.*, 2021, **19**, 5642-5648.

38 M. J. Cabrera-Afonso, A. Sookezian, S. O. Badir, M. El Khatib and G. A. Molander, Photoinduced 1,2-dicarbofunctionalization of alkenes with organotrifluoroborate nucleophiles via radical/polar crossover, *Chem. Sci.*, 2021, **12**, 9189-9195.

39 C. R. Azpilcueta-Nicolas and J.-P. Lumb, Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters, *Beilstein J. Org. Chem.*, 2024, **20**, 346-378.

40 For more details, see the supplementary information.

41 S. Shibutani, T. Kodo, M. Takeda, K. Nagao, N. Tokunaga, Y. Sasaki and H. Ohmiya, Organophotoredox-Catalyzed Decarboxylative C(sp³)-O Bond Formation, *J. Am. Chem. Soc.*, 2020, **142**, 1211-1216.

42 S. Shibutani, K. Nagao and H. Ohmiya, Organophotoredox-Catalyzed Three-Component Coupling of Heteroatom Nucleophiles, Alkenes, and Aliphatic Redox Active Esters, *Org. Lett.*, 2021, **23**, 1798-1803.

43 P.-Z. Wang, B. Zhang, W.-J. Xiao and J.-R. Chen, Photocatalysis Meets Copper Catalysis: A New Opportunity for Asymmetric Multicomponent Radical Cross-Coupling Reactions, *Acc. Chem. Res.*, 2024, **57**, 3433-3448.

Crystal structure of 4b: Ellipsoids are drawn at 30% probability. The phenyl group is disordered over two positions (65:35 ratio). For clarity, hydrogen atoms and the minor position of the phenyl group are omitted. Atom colors: gray (carbon), red (oxygen), blue (nitrogen). For more information, see ESI.