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# Visible Light-promoted C(sp³)-H α-Carbamoylation of Cyclic Ethers with Isocyanides

Camilla Russo, Carmine Volpe, Federica Santoro, Diego Brancaccio, Anna Di Porzio, Alfonso Carotenuto, Antonio Randazzo, Laurence Grimaud, Maxime Vitale, Stefano Protti, et al.

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## To cite this version:

Camilla Russo, Carmine Volpe, Federica Santoro, Diego Brancaccio, Anna Di Porzio, et al. "Visible Light-promoted C(sp³)-H α-Carbamoylation of Cyclic Ethers with Isocyanides." Chemistry - A European Journal, 2024, 30 (48), 10.1002/chem.202401997. hal-04786333

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Distributed under a Creative Commons Attribution 4.0 International License
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# Visible Light-promoted C(sp³)-H α-Carbamoylation of Cyclic Ethers with Isocyanides

Camilla Russo,[a] Carmine Volpe,[a] Federica Santoro,[a] Diego Brancaccio,[a] Anna Di Porzio,[a] Alfonso Carotenuto,[a] Antonio Randazzo,[a] Laurence Grimaud,[b] Maxime R. Vitale,[*b] Stefano Protti,[*c] and Mariateresa Giustiniano*[a]

A protocol exploiting isocyanides as carbamoylating agents for the α-C(sp³)-H functionalization of cyclic ethers has been optimized via a combined visible light-driven hydrogen atom transfer/Lewis acid-catalyzed approach. The isocyanide substrate scope revealed an exquisite functional group compatibility

(18 examples, with yields up to 99%). Both radical and polar trapping, kinetic isotopic effect and real-time NMR studies support the mechanistic hypothesis and provide insightful details for the design of new chemical processes involving the generation of oxocarbenium ions.

## Introduction

Ethers represent valuable functional groups in both organic and medicinal chemistry, where they appear in over two-thirds of FDA approved drugs.[1] Accordingly, the search for new general and green methods to achieve C(sp³)-H functionalization is highly desirable.[2-8] To this end, α-C(sp³)-H carbamoylation reactions represent a poor investigated field, except for a cobalt-catalyzed carbonylative coupling involving carbon monoxide and amines reported by X.-F. Wu (Scheme 1a).[9] Despite the use of a base-metal catalyst and a broad substrate scope both for the ether and the amine coupling partners, the need for high pressure (60 bar) and temperature (120 °C), along with an over-stoichiometric amount of di-tert-butyl peroxide (DTBP), partially limited the greenness of the process. An alternative approach relies on the addition of isocyanides to oxocarbenium ions, generated upon light-triggered oxidation of ethers with a hypervalent iodine (III) reagent (Scheme 1b).[10] However, this method is limited to benzylic ethers and, overall, only three examples have been reported by using either tert-butyl isocyanide or TosMIC (4 equiv. of isocyanide needed; 53–67% yields).

<figure><img src="image_5.png" /><figcaption>Scheme 1. a) Cobalt-catalyzed aminocarbonylation of ethers; b) hypervalent iodine (III) promoted photolytic C(sp³)-H functionalization of benzylic ethers; c) our proposal.</figcaption></figure>

As the results of our interests in the development of visible light-driven strategies involving isocyanides,[8,12] we engaged in the development of a light driven protocol for the C(sp³)-H α-carbamoylation of ethers which would rely on a hydrogen atom transfer (HAT) event followed by a radical polar crossover (RPC) pathway, as proposed in Scheme 1c.[11]

## Results and Discussion

We initially focused on the preparation of amide 8 from tetrahydrofuran (that acts as both starting substrate and reaction medium) and 4-isocyanole biphenyl as the model reaction, and a selection of the obtained results is available in Table 1 (See also Tables S1 and S2 in Supporting Information). Early efforts were based on the hypothesis of a radical addition of an α-oxyalkyl radical to the isocyanide. Thus, the test reactions reported in Table S1 (Supporting Information) were performed in the presence of a hydrogen atom transfer photocatalyst (PC_HAT) and a Lewis acid (LA) such as ytterbium triflate. The latter could activate the isocyanide as an electrophile thus favoring the addition of the nucleophilic α-oxyalkyl radicals).[13–15] Moreover, the Lewis acid could also stabilize the

<footnote>[a] C. Russo, C. Volpe, F. Santoro, D. Brancaccio, A. Di Porzio, A. Carotenuto, A. Randazzo, M. Giustiniano
Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, Italy
E-mail: mariateresa.giustiniano@unina.it</footnote>

<footnote>[b] L. Grimaud, M. R. Vitale
Laboratoire des Biomolécules (LBM), Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005, Paris, France
E-mail: maxime.vitale@ens.psl.eu</footnote>

<footnote>[c] S. Protti
PhotoGreenLab, Department of Chemistry, University of Pavia, viale Taramelli 12, 27100, Pavia, Italy
E-mail: stefano.protti@unipv.it</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202401997</footnote>

<footnote>© 2024 The Author(s). Chemistry - A European Journal 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.</footnote>
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<table><caption>Table 1. Optimization of reaction conditions.</caption><thead><tr><th>Entry</th><th>Isocyanide 1 (Equiv.)</th><th>THF 2</th><th>Yb(OTf)<sub>3</sub> (Equiv.)</th><th>Arylazo sulfones 3-7 (Equiv.)</th><th>Yield (NMR)</th></tr></thead><tbody><tr><td>1</td><td>1</td><td>0.04M</td><td>0.6</td><td>3, m-Cl (1.5)</td><td>39%</td></tr><tr><td>2</td><td>1</td><td>0.04M</td><td>0.6</td><td>4, m-CN (1)</td><td>37%</td></tr><tr><td>3</td><td>1</td><td>0.04M</td><td>0.6</td><td>5, p-OCH<sub>3</sub> (1)</td><td>41%</td></tr><tr><td>4</td><td>1</td><td>0.04M</td><td>0.6</td><td>6, o-OCH<sub>3</sub> (1)</td><td>30%</td></tr><tr><td>5</td><td>1</td><td>0.04M</td><td>0.6</td><td>7, 3,4-di-Cl (1)</td><td>39%</td></tr><tr><td>6</td><td>1</td><td>0.04M</td><td>0.3</td><td>5, p-OCH<sub>3</sub> (1)</td><td>39%</td></tr><tr><td>7</td><td>2</td><td>10 equiv. in cyclo-hexane (0.1M)</td><td>0.3</td><td>5, p-OCH<sub>3</sub> (1)</td><td>ND</td></tr><tr><td>8</td><td>2</td><td>0.04M</td><td>0.3</td><td>5, p-OCH<sub>3</sub> (1)</td><td>90%</td></tr></tbody></table>

generated nucleophilic imidoyl radical intermediate, thus preventing a possible unproductive α-fragmentation pathway to give back the α-oxyalkyl radical and the isocyanide.[8] The use of traditional PC<sub>HAT</sub> such as tetrabutylammonium decatungstate (TBADT), eosin Y (EY), and aromatic ketones (Table S1 in Supporting Information) in tetrahydrofuran (THF) as a solvent afforded the desired product in yields not exceeding the 40%, while any attempt to use THF as a reagent in different solvents (acetonitrile, dichloromethane, toluene, N,N-dimethylformamide, and tert-butanol, Table S1 in Supporting Information), led to detrimental outcomes due to hydrolysis of the Lewis-acid-activated isocyanide to its N-formamide analogue (23–72% depending on reaction conditions, due to adventitious water). On the other hand, the presence of the Lewis acid proved to be key to promote the reaction, since, in its absence, unreacted isocyanide remained detectable by TLC analysis. Other ytterbium sources (e.g., Yb(OAc)<sub>3</sub> and YbCl<sub>3</sub> • 6 H<sub>2</sub>O) as well as different Lewis acids such as Sm(OTf)<sub>3</sub>, Cu(OTf)<sub>2</sub>, La(OTf)<sub>3</sub>, Y(OTf)<sub>3</sub>, and Ag(OTf) led to poorer yields. Based on these observations we reasoned that such results could be improved by promoting the formation of the α-oxyalkyl radical with a stoichiometric hydrogen abstraction promoter. Our attention thus turned on arylazo sulfones, visible light photoactive precursors of aryl radicals, which upon hydrogen abstraction from a suitable H-donor would form inert and volatile aryl derivatives.[16,17] Such reactants, indeed, were known to be efficient H-abstractors with a range of common organic solvents (acetonitrile, chloroform, dichloromethane, ethyl acetate, and acetone), but no reports were available about their ability to promote H-abstraction from ethers such as tetrahydrofuran (BDE (C–H) = 92.0 kcal mol<sup>-1</sup>).[18–20] In this frame, we were encouraged by a test reaction involving isocyanide 1 (1 equiv.) and arylazo sulfone 3 (1.5 equiv.), in the presence of Yb(OTf)<sub>3</sub> (0.6 equiv.) in THF (0.04 M) which afforded the targeted amide 8

in 39% yield after 20 h of irradiation with blue light (30 W LED, Table 1).

We thus investigated different arylazo sulfones, as well as the effects of the molar ratio between the isocyanide and the arylazo sulfone, the catalyst loading, and the solvent medium (Table 1 and Table S2, Supporting Information). Whereas the substitution on the aryl ring of the azo sulfone with either electron-donor or electron-withdrawing groups had negligible effect on the yield, the best reaction conditions were found when 2 equivalents of isocyanide were used and by employing p-methoxy substituted arylazo sulfone 5 as the HAT agent (1 equiv.) and a Lewis acid catalyst loading of 0.3 equiv. (Table 1, Entry 8).

In order to explore the substrate scope of such conditions a library of nineteen amides 8–17 and 19–26 (Scheme 2) featuring both electron-rich (8, 9, 10, 12–14) and electron-poor (11 and 15) aromatic isocyanides, primary (16, 21, 22), secondary (20, 26), and tertiary (19) aliphatic isocyanides and different 5- and 6-membered cyclic ethers (23–26) was prepared, with yields ranging from 45% to quantitative.

Functional group tolerance was good and involved aromatic ethers (10), methyl groups (12, 16, 23), carbamate (13), amine (14), halogen (15), sulfonyl (16), and ester (21, 24) functionalities. Interestingly, when using 2-isocyanobiphenyl as the coupling partner, the reaction afforded exclusively the desired

<figure><img src="image_7.png" /><figcaption>Scheme 2. Optimized reaction conditions and substrate scope (a: reaction run in the absence of both arylazo sulfone and light).</figcaption></figure>
<figure><img src="image_8.png" /></figure>

amide 17, and no traces of phenanthridine derivative 18 were observed.[21] Unfortunately, the reaction with linear ethers such as diethyl ether and tert-butyl methyl ether did not afford the desired amide derivatives, and in this case the aromatic amide formed upon reaction between the isocyanide and the aryl radical from the arylazo sulfone was isolated in 26% yield.[22] Finally, the formation of 26 via α-carbamoylation of isochroman with cyclohexylisocyanide occurred even in the absence of the arylazo sulfone and light probably due to a non-light mediated oxidation of the benzylic ether.

These data led us to propose a mechanistic hypothesis relying on the combination of a HAT process and a Radical Polar Crossover (RPC) pathway as highlighted in Scheme 3.

It is worth noting that oxocarbenium ions generation via visible light triggered methods involving a HAT/RPC sequence has been reported for the synthesis of alkylated azoles, requiring either over-stoichiometric amounts of oxidants (e.g., 3 equiv. of TBHP) or N–F reagents as HAT agents.[23–25] Scheme 3 reports a mechanism for the formation of amide 8.

Under visible light irradiation arylazo sulfone 5 undergoes homolytic fragmentation from its singlet excited state ¹⁵*, to release aryl radical I, nitrogen, and sulfinyl radical II. Aryl radical I abstracts a hydrogen from THF, thus forming α-oxyalkyl radical III, which in turn undergoes a radical recombination with sulfinyl radical II, forming the intermediate V. The latter is subjected to Lewis acid mediated heterolytic fragmentation to give the sulfinate anion VI and oxocarbenium ion VII, further intercepted by the isocyanide 1 to give a nitrilium ion VIII. Finally, hydrolysis of sulfonyl imidate IX affords the amide 8.

Experimental support to this mechanistic hypothesis was provided by the formation of adduct 28 between 1,1,3,3-tetramethylpiperidine N-oxide 27 (TEMPO, 1 equiv.) and THF (Scheme 4a and Figure S1 in Supporting Information) as well as via formation of product 30 upon addition of benzylamine 29 (0.8 equiv.) to oxocarbenium ion VII as detected by means of HRMS (Scheme 4b and Figure S2 in Supporting Information).

<figure><img src="image_9.png" /><figcaption>**Scheme 3.** Mechanistic hypothesis for ethers' C(sp³)-H α-carbamoylation via a HAT/RPC sequence.</figcaption></figure>

a) Radical trapping (α-oxyalkyl radical)

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

b) Polar trapping (oxocarbenium ion)

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

c) Two-step one-pot reaction

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

d) Kinetic isotopic effect

<figure><img src="image_13.png" /><figcaption>**Scheme 4.** Experimental support to the mechanistic hypothesis.</figcaption></figure>

Furthermore, to point out the role of Yb(OTf)₃ in promoting the formation of oxocarbenium ion VII via heterolytic fragmentation, two identical reactions were performed in a one-pot two-step sequence (Scheme 4c), by mixing at first arylazo sulfone 5 alone (i.e., in the absence of the Lewis acid) in THF under irradiation with blue LEDs. One of two reactions was stopped and the analyzed both via HRMS and NMR, confirming the formation of intermediate V (22% yield based on the NMR of the crude mixture, volatile; see Figures S3–S5 Supporting Information). To the second identical reaction, the addition of cyclohexyl isocyanide and Yb(OTf)₃ led the expected amide 20 in 45% yield (based on the NMR of the crude mixture, see Scheme 4c and Figure S4 Supporting Information), thus highlighting the superior performance of the one-pot protocol (93% isolated yield, compound 20 in Scheme 2). Additionally, a real-time NMR analysis of the reaction led to exclude the persistent formation of ytterbium-isocyanide complexes, as the chemical shift of THF, the isocyanide 1, and toluene added as non-complexing reference were all similarly influenced by the paramagnetic effects of ytterbium (See Figures S6 and S7 in Supporting Information). This is in accordance with literature data indicating that a complexation of isocyanides arises from σ-donation from the isocyanide carbon lone pair to the transition metal d-orbitals, coupled with π-donation from the metal to the isocyanide π*-orbital. However, isocyanides are reported in literature as poor π-acceptor ligands (e.g., with respect to CO), thus leading to the formation of reversible complexes with metal ions possessing filled d-orbitals.[15,26,27]
<figure><img src="image_14.png" /></figure>

Additionally, kinetic isotopic effects, observed by performing
the reaction in a 1:1 THF/THF-d₈ solvent mixture and leading to
no evident formation of deuterated adduct, proved that the
rate limiting step was the hydrogen atom abstraction from THF
(Scheme 4d).

Conclusions

In conclusion, the combination of an arylazo sulfone as a HAT
agent and a Lewis acid to promote a radical/polar crossover
pathway, proved to be a valuable visible-light driven approach
enabling a smooth formation of oxocarbenium ions from cyclic
ethers. The isocyanide substrate scope and the functional group
tolerance proved here to be excellent, in contrast with the
limited examples in literature.[10,11] This method interestingly
provides a useful approach to amide derivatives by avoiding
over-stoichiometric coupling agents and expand the chemical
space of electrophilic species (i.e., oxocarbenium ions) suitable
to react with isocyanides in a Passerini-like three-component
reaction.

Acknowledgements

Financial support from Università degli Studi di Napoli “Federico
II”, Napoli, Italy is acknowledged. 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). S.P. acknowledges support from
UniPV and MUR through the program ‘Departments of
Excellence’ (2023-2027). S.P. is grateful to the Italian Ministry for
Universities and Research, PRINPNRR, “Xilonite” project
P2022HSF3R for financial support. Open Access publishing
facilitated by Università degli Studi di Napoli Federico II, as part
of the Wiley - CRUI-CARE agreement.

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available
from the corresponding author upon reasonable request.

Keywords: C–H carbamoylation • Hydrogen atom transfer • Isocyanides • Lewis acid catalysis • Radical polar crossover

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