Synthesis of I(III)/S(VI) reagents and their reactivity in photochemical cycloaddition reactions with unsaturated bonds

The development of novel methodologies for the introduction of the sulfoxonium group under mild conditions is appealing but remains underexplored. Herein we report the synthesis of a class of hypervalent iodine reagents with a transferrable sulfoxonium group. These compounds enable mixed iodonium-sulfoxonium ylide reactivity. These well-defined reagents are examined in visible-light-promoted cyclization reactions with a wide range of unsaturated bonds including alkenes, alkynes, nitriles, and allenes. Two distinct cyclization pathways are identified, which are controlled by the substituent of the unsaturated bond. The cycloaddition protocol features simple operation, mild reaction conditions, and excellent functional group tolerance, affording a broad range of sulfoxonium-containing cyclic structures in moderate to excellent yields. Furthermore, the sufoxonium group in the product can be transformed into diverse functional groups and structural motifs via single electron transfer and transition-metal catalysis.


Synthesis of the I (III) /S (VI) reagent
In sulfoxonium ylide-mediated insertion reactions, the sulfoxonium group inevitably falls off to give the key carbene intermediate. To access structurally complex sulfoxonium compounds, we decided to develop a sulfoxonium transfer process using an I (III) /S (VI) reagent. Hypervalent iodine (III) reagents have attracted widespread interest in the synthetic community owing to their capability of transferring functional groups of the same oxidation state 47,48 . In this context, several examples of defined hypervalent iodine reagents containing transferable hypervalent functional groups such as phosphonium [49][50][51] and arsonium groups 52,53 have been successfully developed for use in single-electron transfer (SET) or electrophilic substitution reactions. Among them, sulfur-containing hypervalent iodine reagents remains scarcely investigated and only one sulfonium variant has been reported by Podrugina and co-workers 54 . However, this S (IV) embedded structure was reported to be highly unstable above −10°C and unable to be isolated. Little was known of its reactivity. We envisaged that a sulfoxonium substitution with a higher S oxidation state might stabilize the negative charge of ylide carbon, offering both stability and new reactivity of I, S-mixed ylides. In this context, we report the design, synthesis, and X-ray structural characterization of I (III) /S (VI) reagents and their use in photochemical cycloaddition reactions with various unsaturated bonds to afford [3 + 2] or [4 + 2] products containing sulfoxonium functionality (Fig. 1c).
Our initial efforts focused on the synthesis of the I (III) /S (VI) reagent 3 (Fig. 2). Concerning the stability of 3, we decided to first synthesize cyclic analogs with a stabilizing ortho-carboxylate group, a trick often applied to I (III) compounds 47 . 1-Acetoxy-1,2-benziodoxol-3(1H)-one 1a underwent smooth ligand exchange with α-ketosulfoxonium ylides 2 to give the desired products 3a and 3b in moderate yield using pyridine and trimethylsilyl triflate (Fig. 2). These compounds are white solids and have reasonable stability in either the solid state or in solution at ambient temperature over an extended time. The corresponding acyclic analogs were prepared from diacetoxyiodobenzene 1b using a strong Brønsted acid. Excellent yields were obtained on gram scales (see Supplementary Methods for more details). These acyclic reagents (3c-3w) are relatively less stable compared to 3a and 3b. They could be stored at −20°C for several weeks, but gradually decompose at room temperature in a solid state. The counterion of these iodonium salts affects stability, wherein hexafluorophosphates 3c and tetrafluoroborates 3e are more stable than triflates 3d. Versatile substituted aryl-and heteroaryl-derivatives were prepared (3f-s), as well as alkyl substituted analogs (3t, u) using a set of uniform conditions.

Reaction optimization
We next turned our attention to exploring the reactivity of the synthesized I (III) /S (VI) reagents. Considering the high leaving group ability of I (III)57 , we envisioned that these molecules might be activated under photochemical conditions, enabling a sulfoxonium transfer to common chemical feedstocks via a sulfoxonium-substituted reactive intermediate. Inspired by the early work of Murphy and co-workers that employed blue LED (light emitting diode) to promote cyclopropanation of iodonium ylides with alkenes 58 , we commenced to explore the chemical reactivity of 3c towards 4.0 equiv. of 1-hexene in MeCN under blue LED (1 W, λ max 452 nm) irradiation. To our delight, the photocycloaddition occurred smoothly to afford [4 + 2] product 5c in 95% isolated yield ( Table 1, entry 1). To the best of our knowledge, this benzo-fused cyclic compound is a rare example of ketyl alkyl substituted sulfoxonium ylide. The counter ion of acyclic reagents (3d and 3e) had a moderate effect on the overall conversion (entries 2 and 3). No desired product was detected using the neutral cyclic reagent 3a, likely due to the lower tendency for neutral I (III) to be excited under visible light (entry 4). Solvent screening indicated that halogenated solvents such as DCM decreased reaction efficiency (entry 7). When MeOH was used, neither 5c or O-H insertion products was detected (entry 6). The [4 + 2] cycloaddition becomes sluggish under aerobic condition and no product was formed in the dark (entry 7 and 8). Using 2 equiv. of 1-hexene and irradiating the reaction mixture with white LED lead to slightly lower yields, and very little improvement was realized when prolonging the reaction time to 5 h (entries 9-11).

Examination of substrate scope
Having the optimized conditions in hand, we turned our attention to the substrate scope and limitations of the light-mediated tandem [4 + 2] cycloaddition of unactivated alkenes feedstocks 4 with reagent 3, and the results are summarized in Fig. 3. We were glad to find that this method was able to convert alkene feedstocks containing different straight-chain alkyl substrates into cyclic sulfoxonium ylides, with excellent chemoselectivity (5a-g). The functional group tolerance of this transformation is illustrated using substrates bearing cycloalkanes (5 h), aromatic rings (5i, j), ethers (5k), esters (5l, m), sulfonates (5n), sulfones (5o), and silanes (5p). The regioselectivity of this reaction was confirmed by converting product 5i to a known product (see Supplementary Methods for more details). Furthermore, directing groups were not needed to ensure site-selectivity for a substrate bearing two reactive alkenes (5q). Only the electron-rich terminal alkene was selectively cyclized. E/Z-mixtures of 4r (E/Z = 50:50) and 4s (E/Z = 63:37) resulted in the exclusive formation of trans-substituted 5r and 5s, respectively. These results demonstrated the feasibility of conducting a stereoconvergent cycloaddition reaction. Additional control experiments showed that alkene photoisomerization was not responsible for the stereochemical outcome observed with 5r and 5s. Cyclopentene, cyclohexene, and norbornene led to multi-fused cyclic products 5t, 5u, and 5v in 40%, 60%, and 80% yields, respectively. The crystal structure of 5u unambiguously confirmed these compounds as in cis-configuration. Moreover, 1,1-disubstituted alkene could react smoothly to give product 5w with a quarternary carbon center in high efficiency. Substrates with either methyl or cyclohexyl substituent at the 4-position of the phenyl ring respectively gave 5x in 70% and 5y in 90% yield. Decreasing the electron density on the phenyl group slowed down the cycloaddition and yields were attenuated (5z). Regarding ylides containing more than one nucleophilic site, the reaction afforded products as a mixture of isomers (5aa, ab). Furthermore, our strategy permitted the use of a diverse range of heteroarenes, enabling [4 + 2] processes with thiophenyl (5ac, ad), benzothiophenyl (5ae), and furyls (5af).
When styrene derivatives were used as a C 2 synthon in the photocyclization reaction, instead of getting the 6-membered ring sulfoxonium ylides, we exclusively isolated dihydrofuranyl sulfoxonium products (Fig. 4). After irradiating with blue LED for 3 h, 3c reacted with 1,1-diphenylethylene to give tri-substituted dihydrofuran 7a in 95%    yield. Other styrene derivatives, including those containing halogen (7b), phenyl (7c, d), ether (7e), and alkyl (7f) were well tolerated. It is possible that during this [3 + 2] cyclization event, the stability of the in situ generated carbocation dictated the cyclization point. When styrene was employed, the more stable benzylic cation reacted with the oxygen nucleophile (ketone), while a more reactive alkyl cation intermediate was preferentially incepted by the aromatic π-electrons in a Friedel-Crafts manner 59,60 . Ylides bearing a strong electronwithdrawing cyano-group exhibited poor reactivity, resulting in a 28% yield of 7g. This procedure was successfully applied to a wide range of reagents 3 functionalized with 1-naphthyl (7h), thiophenyl (7i), furyl (7j), and benzyl (7k). 1,1-Disubstituted olefins, which are commercially available or easily accessible from acetophenone, were suitable substrates (7l-n). When 1,2-disubstituted styrenes were used, a synthetic challenging tetrasubstituted dihydrofuran scaffold was prepared (7o and 7p) It is noteworthy that this [3 + 2] process is steoreoconvergent and only the trans-isomers were obtained exclusively, which was confirmed by X-ray diffraction analysis of 7p. Stilbene and βmethylstyrene with either olefin conformation (E or Z) delivered transproducts only (7o and 7p, respectively). (1-Cyclopropylvinyl)benzene reacted smoothly with 3c to the desired [3 + 2] product 7q, with no ring-opening product detected. This result suggests the corresponding benzylic radical was unlikely involved in this process.
To further explore the reactivity of reagent 3 under visible light radiation, we tested reactions against other unsaturated bonds, such as nitriles, alkynes, and allenes (Fig. 5). Due to the inert reactivity of nitriles, similar cyclization reactions under blue LED did not happen. To our delight, subjecting the I, S-ylide to nitrile as solvent under the irradiation of purple LED or in the presence of Rh 2 (OAc) 4 at 25°C led to a smooth conversion to the [3 + 2] cycloadduct, isoxazolyl sulfoxonium salts (9a-f) in high yields. More reactive alkynes were converted to multisubstituted furans following the [3 + 2] pathway (10a-c). Reactions of alkyl acetylenes afforded cyclic vinyl,ketyl-disubstituted sulfoxonium ylides via [4 + 2] (11a-c). When allenes were tested, the [4 + 2] cycloaddition at the terminal double bond occurred, resulting in product 13 in 72% yield. It is noteworthy that the reactions involving alkynes and allenes were carried out using acetonitrile as solvent indicating the reactivity of I (III) /S (VI) reagents was highly selective toward carbon-carbon triple bonds. Structurally sophisticated sulfoxonium molecules could be conveniently prepared, which would be highly challenging using existing methods.

Mechanistic investigations
Mechanistic aspects of the photocycloaddition were investigated. For the [4 + 2] reaction using aliphatic alkenes, no desired products were formed in the presence of metal catalysts (Rh and Cu) or under dark conditions. When TEMPO was added as a radical scavenger, the desired reaction was suppressed (Fig. 6a, left). In contrast, the [3 + 2] cycloaddition involving 1,1-diphenylethylene (6a) could be promoted by these transition metals in the absence of light, albeit in slightly decreased yields (85% using Rh and 60% using Cu). Interestingly, the [3 + 2] cycloaddition was not significantly affected by TEMPO (Fig. 6a,  right). These results indicated that two distinct reaction pathways were operative when aliphatic olefins and styrenes were used, respectively. Likely, the [4 + 2] cycloaddition involved radical intermediates and the [3 + 2] reaction was carbene/carbenoid mediated. The complete chemical reactivity was remarkable. The stereodivergent nature of both cycloadditions, when E and Z-alkenes were used, indicated a stepwise cyclization. Furthermore, we observed a substantial decrease in yield when I (III) /S (VI) reagents contained an electron-withdrawing group on the aryl moiety (Fig. 6b), suggesting the involvement of cations. We carried out a photo-promoted [4 + 2] reaction using an allyl amide substrate, in which the amide oxygen would intercept a cation, but not a radical. As expected, the reaction produced the corresponding oxazoline product 13 cleanly (Fig. 6c). We suspected that the cation species for both reaction pathways might be formed by the heterolytic opening of a donor-acceptor cyclopropane intermediate formed by photo-promoted addition of I, S-ylide to olefin. Unfortunately, we could not isolate this key species in these intermolecular reactions. Interestingly, intramolecular reactions did deliver the desired cyclopropane products 14, providing support for this hypothesis (Fig. 6d). Further studies are currently underway to fully elucidate the mechanistic details for the carbon-carbon forming processes and substrate-controlled reaction pathway divergence.

Synthetic derivatizations
The sulfoxonium products were demonstrated as versatile substrates for various transformations. As shown in Fig. 7, product 5i was reduced to cyclic ketone 15 using Raney-Nickel in refluxing isopropanol. Protonation of sulfoxonium ylide 5i with HOTf gave the corresponding sulfoxonium salt (16) in 90% yield and with a 1:1.5 dr ratio. The in situ generated sulfoxonium salt was converted into sulfide 17 in high dr using a Brønsted acid. Compound 7a was a competent electrophile in palladium-catalyzed cross-coupling reactions, leading to the formation of coupled product 18. The sulfoxonium functionality was demethylated by heating with KI in acetone, giving sulfoxide 19. Additionally, sulfoxonium could undergo SET processes using photoredox catalysis to generate the corresponding vinyl radical, which was functionalized to give vinyl dihydrofuran 20 in 70% yield. This oxidative radical polar crossover reaction was a rare example of using sulfoxonium as an oxidative radical precursor 61-63 .

Discussion
We designed and synthesized an I (III) /S (VI) reagent for sulfoxonium transfer reactions. These molecules revealed mixed I, S-ylide characteristics and demonstrated remarkable photocycloaddition reactivity towards a broad scope of unsaturated bonds under ambient blue LED radiation without the need for any catalyst and photosensitizer. Unusual chemical selectivity was observed, which was controlled by the type of unsaturated bonds. For aliphatic substituted double and triple bonds, a formal [4 + 2] cycloaddition occurred to give cyclic ketyl alkyl/vinyl sulfoxonium ylide products. When aryl-substituted unsaturated bonds were employed, a [3 + 2] prevailed, delivering structurally exotic cyclic vinyl sulfoxonium salts. The diverse reactivity of the sulfoxonium functionality in the products could be exploited in further chemical derivatizations.

Methods
General procedure for photochemical cycloaddition reaction with I (III) /S (VI) reagents In a typical experiment, to a 10 mL oven-dried tube equipped with a stirring bar was added reagent 3e (108.8 mg, 0.2 mmol), cyclohexene 4u (65.7 mg, 0.8 mmol), anhydrous MeCN (1.0 mL). The reaction vial was capped with a rubber septum under an argon atmosphere, and it was fixed on a SynLED 4 × 4 photoreactor (SynLED discover TM 452 nm, 1 W, designed and manufactured by Shenzhen SynLED Tech. Ltd.) for 5 h. The solvent was removed under vacuum and the crude mixture was purified by flash column chromatography to yield the corresponding products 5u (33.1 mg, 60%). The reactions with other kinds of unsaturated compounds were carried out similarly and the procedures are presented in Supplementary Methods.

Data availability
Detailed experimental procedures and characterization of structurally novel compounds, mechanistic studies, and DFT calculation results are available in Supplementary Methods. For NMR spectra of structurally novel compounds, see Supplementary Figures. The crystallographic data generated in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 2068912 (3b), 2068911 (3e), 2128359 (5 u), 2128864(7p) 2152681 (9e), 2144537 (11a). These crystallographic data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http:// www.ccdc.cam.ac.uk/data_request/cif. Further relevant data are available from the corresponding author upon request.