Ahmed Chaambi

Gulbin Kürtay

Raoudha Abderrahim

Frédéric Robert

Yannick Landais
email: yannick.landais@u-bordeaux.fr

Aryl radical-mediated Free-radical alkenylation of Alkyl Halides

Keywords: Aryl radical, alkenylation, diaryliodonium, Electron Donor-Acceptor, vinylsulfone

Free-radical alkenylation of a range of alkyl iodides has been carried out leading to the desired olefins in moderate to good yields under mild conditions. The process is initiated by an aryl radical which abstracts the iodide from the alkyl iodide to form a C-centered radical intermediate, the addition of which onto a vinylsulfone providing the final vinylsulfone. The aryl radical is generated in situ through a single-electron transfer from an electron donor-acceptor complex (EDA) formed between a diaryliodonium salt (Ph2I + -PF6 -) and triethylamine.

Introduction

Free-radical alkenylation (also called vinylation) of alkyl halides constitutes a powerful C-C bond forming process offering an access to a wide range of olefins. [START_REF] Baldwin | Applications of consecutive radical addition-elimination reactions in synthesis[END_REF][START_REF] Takami | Radical Alkenylation of -Halo Carbonyl Compounds with Alkenylindiums[END_REF][START_REF] Takami | Radical Allylation, Vinylation, Alkynylation, and Phenylation Reactions of -Halo Carbonyl Compounds with Organoboron, Organogallium, and Organoindium Reagents[END_REF][START_REF] Bertrand | A New Radical Vinylation Reaction of Iodides and Dithiocarbonates[END_REF][START_REF] Rouquet | Allylsilanes in « Tin-free » Oximation, Alkenylation and Allylation of Alkyl halides[END_REF][START_REF] Keck | A Free Radical Addition-Fragmentation Reaction for the Preparation of Vinyl Sulfones and Phosphine Oxides[END_REF][START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF][START_REF] Subramanian | Radical Addition Reactions' in Comprehensive Organic synthesis[END_REF] The reaction proceeds through the addition of a Ccentered radical IV, generated from an alkyl halide precursor I, onto an olefinic acceptor II. This leads to a new radical intermediate V, affording the final unsaturated system III through β-elimination (Figure 1). [START_REF] Baldwin | Applications of consecutive radical addition-elimination reactions in synthesis[END_REF][START_REF] Bertrand | A New Radical Vinylation Reaction of Iodides and Dithiocarbonates[END_REF][START_REF] Rouquet | Allylsilanes in « Tin-free » Oximation, Alkenylation and Allylation of Alkyl halides[END_REF][START_REF] Keck | A Free Radical Addition-Fragmentation Reaction for the Preparation of Vinyl Sulfones and Phosphine Oxides[END_REF][START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF] Among the broad range of alkenyl acceptors (varying the Y substituent), sulfur derivatives, [START_REF] Rouquet | Allylsilanes in « Tin-free » Oximation, Alkenylation and Allylation of Alkyl halides[END_REF][START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF][START_REF] Russell | Alkylation of -Substituted Styrenes by a Free Radical Addition-Elimination Sequence[END_REF][START_REF] Miyamoto | The Reaction of Styryl Sulfoxides or Sulfones with Boranes[END_REF][START_REF] Beniazza | Free-Radical Carboalkenylation of Olefins: Scope, Limitations and Mechanistic Insights[END_REF] and in particular vinylsulfones, [START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF][START_REF] Beniazza | Free-Radical Carboalkenylation of Olefins: Scope, Limitations and Mechanistic Insights[END_REF][START_REF] Russell | Reactions of Alkylmercurials with Heteroatom-Centered Acceptor Radicals[END_REF][START_REF] Xiang | Stereospecific Alkenylation of C-H Bonds via Reaction with -Heteroatom-Functionalized Trisubstituted Vinyl Triflones[END_REF][START_REF] Noble | Photoredox α-Vinylation of α-Amino Acids and N-Aryl Amines[END_REF][START_REF] Amaoka | Photochemically induced radical alkenylation of C(sp3)-H bonds[END_REF][START_REF] Corcé | Silicates as Latent Alkyl Radical Precursors: Visible-Light Photocatalytic Oxidation of Hypervalent Bis-Catecholato Silicon Compounds[END_REF] have attracted the most interest due to their easy accessibility and relative innocuousness. The generation of radical precursors IV from alkyl halides I generally implied the use of tin reagents such as R3SnSnR3 (R=Me, nBu) to initiate the reaction. [START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF] In this efficient process, the released sulfonyl radical (Y = SO2R') was shown to react with ditin, forming a new R3Sn radical, which sustained the radical chain. [START_REF] Baldwin | Applications of consecutive radical addition-elimination reactions in synthesis[END_REF][START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF][START_REF] Subramanian | Radical Addition Reactions' in Comprehensive Organic synthesis[END_REF] However, due to the perceived toxicity of tin reagents and the contamination of final products with tin residues, alternative strategies have been developed using for instance the Pd/light-initiated radical reactions, as recently reported by Ryu and co-workers. [START_REF] Sumino | Palladium/Light Induced Radical Alkenylation and Allylation of Alkyl Iodides Using Alkenyl and Allylic Sulfones[END_REF] Figure 1. General free-radical alkenylation of alkyl halides.

In the course of our studies on multi-component olefin carbo-functionalization processes, [START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF][START_REF] Beniazza | Free-Radical Carboalkenylation of Olefins: Scope, Limitations and Mechanistic Insights[END_REF] we also devised recently a radical alkenylation of alkyl iodides, in which aryl radicals, generated in situ from boronic acids, were used as initiators. [START_REF] Hara | Boronic Acid Mediated Carbocyanation of Olefins and Vinylation of Alkyl Iodides[END_REF] The highly reactive aryl radicals are known to abstract iodine atom from alkyl iodides with rate constant close to k ~ 10 9 M -1 s -1 , [START_REF] Heinrich | Intermolecular Olefin Functionalisation Involving Aryl Radicals Generated from Arenediazonium Salts[END_REF] a fast process which outperforms all other competitive processes that might occur in the reaction medium. Using this method, carbo-cyanation of olefins and addition of alkyl iodides to vinylsulfones were carried out, affording respectively the desired nitriles and olefins in moderate to good yields. Although efficient, the generation of the aryl radical requires the use of an excess of the costly t-BuON=NOt-Bu (DTBHN), as the reaction is a non-chain process, the released PhSO2 radical being unable to regenerate the aryl radical from phenylboronic acid. In the course of our search for a better source of aryl radicals, our attention was drawn by recent studies on electron donor-acceptor complexes (EDA) formed between diaryliodonium salts (Ph2I + -OTf) and electron donors. [START_REF] Lima | Organic Synthesis Enabled by Light-Irradiation of EDA Complexes: Theoretical Background and Synthetic Applications[END_REF][START_REF] Fouassier | Photoinitiators for Polymer Synthesis: Scope, Reactivity and Efficiency[END_REF][START_REF] Tobisu | Visible Light-mediated Direct Arylation of Arenes and Heteroarenes Using Diaryliodonium Salts in the Presence and Absence of a Photocatalyst[END_REF][START_REF] Noël-Duchesneau | Metal-Free Synthesis of 6-Phosphorylated Phenanthridines: Synthetic and Mechanistic Insights[END_REF][START_REF] Lecroq | Visible-Light-Mediated Metal-Free Synthesis of Aryl Phosphonates: Synthetic and Mechanistic Investigations[END_REF] Such complexes were shown to provide aryl radicals upon single electron transfer (SET) under thermal or photochemical activation (Figure 2). [START_REF] Wen | Direct Arylation of Arene and N-Heteroarenes with Diaryliodonium Salts without the Use of Transition Metal Catalyst[END_REF][START_REF] Wang | Transition Metal-Free Direct C-H Functionalization of Quinones and Naphthoquinones with Diaryliodonium Salts: Synthesis of Aryl Naphthoquinones as β-Secretase Inhibitors[END_REF] Lakhdar and co-workers elegantly illustrated the reactivity of these EDA complexes and the utility of aryl radicals for the generation of phosphynoyl radicals and their subsequent reaction with isonitriles. [START_REF] Noël-Duchesneau | Metal-Free Synthesis of 6-Phosphorylated Phenanthridines: Synthetic and Mechanistic Insights[END_REF] Earlier, Chatani et al described the arylation of pyrroles and the generation of aryl radicals through a charge transfer complex between a diaryliodonium salt and electron-rich pyrroles. [START_REF] Tobisu | Visible Light-mediated Direct Arylation of Arenes and Heteroarenes Using Diaryliodonium Salts in the Presence and Absence of a Photocatalyst[END_REF] Based on these premises, we devised an efficient modification of our aryl-mediated alkenylation of alkyl iodides, based on the generation of a phenyl radical from an EDA complex resulting from the association between Ph2I + , -PF6 and Et3N. A scope and limitation of the methodology is provided and a mechanism based on literature precedent and isolation of byproducts is proposed to rationalize the course of the reaction between alkyl halides 1 and bis-sulfone 2 (Figure 2).

Results and Discussion

Based on previous studies on the generation of aryl radicals from iodonium salts-Amine EDA complexes, [21,23- 24] we first optimized the process, using cyclohexyl iodide 1a as an alkyl iodide model, bis-sulfone 2, Ph2I + , -PF6 and Et3N as the electron donor in DMF. Results are summarized in Table 1. The reaction was first performed at 65°C in the presence of 1.5 equiv. of Ph2I + PF6 -, and 2 equiv. of Et3N, leading to the formation of the expected olefin 3a in 52% isolated yield (Table 1, entry 1). When the reaction was repeated under similar conditions but in the absence of Et3N, 3a was not formed showing the importance of the amine for a smooth running of the reaction (Table 1, entry 2). The addition of a large excess of Et3N led to a slight but not significant increase in yield (Table 1, entry 3). Under the same conditions, but under visible-light irradiation at room temperature, using a blue LED lamp at 433 nm, the reaction led to 3a with the same yield (Table 1, entry 4). During reactions above, we also noticed the formation of various amount of PhSO2Ph, likely arising from the reaction between the released PhSO2 group from bis-sulfone 2 and Ph2I + , -PF6 , [START_REF] Umierski | Metal-Free Synthesis of Diaryl Sulfones from Arylsulfinic Acid Salts and Diaryliodonium Salts[END_REF] indicating that a part of the iodonium reagent was consumed in undesired processes. The reaction was thus repeated using an excess of Ph2I + , -PF6 (3 equiv.) under thermal activation, which resulted in the formation of 3a in a more satisfying 80% yield (Table 1, entry 5). These optimized conditions were then used in the following investigations. Table 1. Optimization of the alkyl iodides alkenylation process.

Entry [a] [a] The reaction was carried out using 1a (0.5 mmol), 2 (1 mmol) in DMF in the presence of Ph2I + , -PF6 and Et3N under thermal conditions. [b] The reaction was performed under visible light irradiation (blue LED (433 nm).

The optimized conditions of the alkenylation reaction were extended to several alkyl iodides 1b-k leading to vinylsulfones 3b-k with moderate to good yields (Scheme 1). Alkyl radicals, whether primary, secondary or tertiary, all react effectively with bis-sulfone 2, although with slightly lower yields in general for the former. As mentioned before, in all reactions, PhSO2Ph was also formed with yields ranging between 50-55%, but was easily discarded from the desired olefins, through silica gel chromatography. Starting from diastereomerically pure menthyl iodide 1k, the corresponding olefin 3i was obtained in good yield and high diastereocontrol, with the stereochemistry as shown. A 6:4 diastereomeric mixture of 3β-iodo-5α-cholestane 1j, [START_REF] Ortega | Iron (III)-Catalyzed Halogenations by Substitution of Sulfonate Esters[END_REF] under similar conditions led to olefin 3j as a 6:4 mixture of diastereomers. Finally, it is worth noticing in the case of n-hexyl iodide 1k, the formation of hexylphenylsulfone 4, along with the desired product 3k. The isolation of such an alkylsulfone from primary iodide 1k was not observed with secondary and tertiary iodides, pointing toward a SN2 type reaction between iodide 1k and a putative phenylsulfinate anion. [START_REF] Simpkins | Sulphones in Organic Synthesis[END_REF] The presence of the latter, tentatively rationalized below, could also explain the formation of PhSO2Ph through reaction with excess Ph2I + , -PF6 (vide infra). [START_REF] Umierski | Metal-Free Synthesis of Diaryl Sulfones from Arylsulfinic Acid Salts and Diaryliodonium Salts[END_REF] Scheme 1. Ph2I + , -PF6 -Et3N mediated alkenylation of alkyl halides.

Based on experimental evidences, and drawing on the studies of Lakhdar and co-workers, [START_REF] Noël-Duchesneau | Metal-Free Synthesis of 6-Phosphorylated Phenanthridines: Synthetic and Mechanistic Insights[END_REF] a mechanism for this radical alkenylation is proposed in Figure 3. The reaction likely begins with the association between Et3N and Ph2I + PF6 -, resulting in the corresponding strongly colored EDA complex A (eq. 1). Single-electron transfer from A under thermal activation likely generate the required phenyl radical. Absorption of the EDA complex in the visible region also allowed its activation and the SET process to occur using simple blue LEDS, albeit with generally lower yields and longer reaction time. The aryl radical then abstracts the iodine atom from the alkyl iodide 1 to form the alkyl radical R (eq. 2), which is trapped by the bis-sulfone 2, affording the desired product 3 and the phenylsulfonyl radical (eq. 3). [START_REF] Hara | Boronic Acid Mediated Carbocyanation of Olefins and Vinylation of Alkyl Iodides[END_REF] As mentioned above, the formation of both PhSO2Ph and the alkylsulfone 4 may be rationalized by the formation at some stage of a phenylsulfinate anion (eq. 6 and 7 respectively). A putative recombination between n-hexyl or phenyl radicals and the PhSO2 radical, is unlikely considering the low concentration of these radical species in the reaction medium. Several pathways maybe envisioned to explain the formation of PhSO2 -. Phenylsulfonyl radical is known for its ability to abstract allylic hydrogens to form PhSO2H, [START_REF] Markovic | Allyl, Methallyl, Prenyl, and Methylprenyl Ethers as Protected Alcohols: Their Selective Cleavage with Diphenyldisulfone under Neutral Conditions[END_REF][START_REF] Markovic | Mechanism of the Diphenyldisulfone-Catalyzed Isomerization of Alkenes. Origin of the Chemoselectivity: Experimental and Quantum Chemistry Studies[END_REF] then leading to the corresponding sulfinate in the presence of excess Et3N. Hydrogen abstraction from vinylsulfone products 3 was ruled out due to the absence of clear evidence of isomerized products including allylsulfones in the medium. However, an alternative hydrogen transfer seemed more favorable considering the presence of the Et3N +. radical-cation i formed in the first step (eq. 1). Recent studies indicate that the C-H bond α to nitrogen in the aminium i is significantly weakened with a BDE estimated to ~42 kcal/mol. [START_REF] Beatty | Amine Functionalization via Oxidative Photoredox Catalysis: Methodology Development and Complex Molecule Synthesis[END_REF] Such a weak bond and the expected high concentration of the aminium i in the medium would thus allow an hydrogen atom abstraction [START_REF] Beatty | Amine Functionalization via Oxidative Photoredox Catalysis: Methodology Development and Complex Molecule Synthesis[END_REF][START_REF] Capaldo | Hydrogen Atom Transfer (HAT): A Versatile Strategy for Substrate Activation in Photocatalyzed Organic Synthesis[END_REF][START_REF] Hu | The chemistry of amine radical cations produced by visible light photoredox catalysis[END_REF] by the PhSO2 radical, leading to iminium ii and PhSO2H (eq. 4), then to the corresponding sulfinate iii through deprotonation by excess Et3N (eq. 5). Although we were unable to isolate diethylamine and acetaldehyde resulting from the hydrolysis of iminium ii upon work-up, this route appears reasonable to explain the presence of PhSO2Ph and sulfone 4 in large amount.

Conclusions

In summary, we have reported a straightforward alkenylation of alkyl halides, mediated by aryl radicals. The latter are generated through a SET process from an EDA complex formed in situ between a diaryliodonium salt (acceptor) and Et3N (electron-donor). An excess of both the iodonium salt and the amine are required to reach good yields of olefins, as a portion of the iodonium salt is consumed through a side-reaction involving a phenylsulfinate, generated during the reaction. The latter may thus react with more reactive primary iodides through a SN process, explaining lower yields in these cases as compared to those obtained with secondary and tertiary iodides. Despite the modest yields with primary iodides, good yields of olefins are obtained starting from commercially available reagents. Other sulfonyl acceptors, [START_REF] Ovadia | Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives[END_REF] including cyanides, oximes and alkynes should react under these conditions, which are now studied in our laboratory and will be reported in due course.

Experimental Section

Diphenyliodonium hexafluorophosphate alkenylation of alkyl iodides -General procedure

A single-neck-round-bottomed flask was charged with the corresponding alkyl iodide 1 (0.5 mmol), the E-1,2bis(phenylsulfonyl)ethylene 2 (1 mmol), the diphenyliodonium hexafluorophosphate (1.5 mmol), triethylamine (1 mmol) and DMF (0.2 M). The reaction mixture was degassed by three consecutive freeze/pump/thaw cycles. The flask was sealed under vacuum, and the reaction mixture was heated at 65°C for 15 to 24 h (depending on the completion of the reaction monitored by TLC) under an argon atmosphere. The reaction was then quenched with a 0.1M HCl solution (10 mL) then extracted with CH2Cl2 (3x20 mL). After separation of the aqueous layer, the organic layer was saturated with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The target compound 3 was finally obtained by column chromatography using the adequate petroleum ether: ethyl acetate mixtures as the eluent.

Figure 2 .

 2 Figure 2. EDA complex and generation of aryl radicals. Application to the alkenylation of alkyl iodides.

Figure 3 .

 3 Figure 3. Mechanism of the aryl radical-mediated alkenylation of alkyl iodides.

Author Contribution Statement G. K. and A. C. contributed equally and performed the experiments and characterization of all materials. Y. L. and F. R. supervised the work and wrote the article. All authors commented on the manuscript.