Abstract
Skeletal editing of single-atom insertion to basic chemicals has been demonstrated as an efficient strategy for the discovery of structurally diversified compounds. Previous endeavors in skeletal editing have successfully facilitated the insertion of boron, nitrogen, and carbon atoms. Given the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion like Baeyer-Villiger reaction is of particular significance. Herein, we present an approach for the skeletal modification of styrenes using O2 via oxygen insertion, resulting in the formation of aryl ether frameworks under mild reaction conditions. The broad functional-group tolerance and the excellent chemo- and regioselectivity are demonstrated in this protocol. A preliminary mechanistic study indicates the potential involvement of 1,2-aryl radical migration in this reaction.
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Introduction
Over the past few years, molecular skeletal editing has emerged as a potent tool, facilitating the construction of structurally diversified molecules derived from common synthetic scaffolds1. Compared with the traditional de novo synthesis approach, direct modification of the molecular structure obviates the resource and time-consuming of constructing a library of complex molecular and may extend the chemical space2,3,4,5,6,7,8,9. However, it is still a challenging issue because the selective modification of inert C-C bonds is required in complicated reaction systems. Despite these challenges, some significant achievements have been reported in the context of formal-single-atom skeletal editing including boron10,11, carbon12,13,14,15,16,17, or nitrogen18,19,20,21 atom insertion and deletion reaction22,23,24,25,26,27,28 (Fig. 1a). Considering the prevalence of oxygen atom in biological active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion holds particular significance, which is also very important for bioactive compound modification and drug discovery29,30,31,32. One classic reaction fitting this description is the Baeyer-Villiger reaction, which has been widely used in organic synthesis to convert ketones into esters or lactones through a single-oxygen-atom insertion process (Fig. 1b)33,34. Notably, a formal oxygen insertion into C-C bond of arenes through cascade reactions of arenophile-based cycloaddition, epoxidation, and cycloreversion was recently reported by Sarlah and colleagues (Fig. 1c)35. Despite previous significant progress, there is room for expanding the concept of single-oxygen-atom insertion into other types of C-C bonds, particularly through the utilization of O2 or even air as a green and ideal oxygen source36,37,38,39,40.
a skeletal editing through direct boron, carbon, and nitrogen insertion. b single-oxygen-atom insertion through Baeyer-Villiger reaction. c two-step formal oxygen-atom insertion of the arene. d direct oxygen insertion into Ar-C(sp2) σ-bond.
Alkene is one of the most important classes of chemicals in the chemical industry and synthetic community41,42,43. Significant oxygenation of olefins at the relatively active C = C double bond and allylic C-H bond including classical Wacker oxidation44,45, epoxidation46,47,48,49, oxidative cleavage of alkene50,51, and C-H bond oxygenation37,52,53,54,55,56,57,58 have been developed and widely used in synthetic chemistry. Despite these notable achievements, no other oxygenation pathway for olefins has been disclosed in recent decades. Although someAr-C(sp2) bond functionalization transformations have been elegantly realized by groups such as Youn59, Schoenebeck and Lautens60, Wei and Duan61, and our own group62. Herein, we present an efficient skeletal editing of alkenes through Ar-C(sp2) σ-bond oxygenation of alkene for the synthesis of highly value-added ether products (Fig. 1d), which widely exist in natural products, pharmaceuticals, and agrochemicals29,30. By utilizing air or dioxygen as the O-source, this chemistry provides an alternative approach to aryl ether synthesis under metal-free and mild reaction conditions. The mode of C-C bond activation would open avenues for future research in alkene chemistry.
Results
To implement this concept, we conducted a preliminary investigation using 4-methylstyrene 1a and Tosyl chloride (TsCl) 2a as the model substrates for reaction discovery and optimization. To our delight, the desired Ar-C(sp2) σ-bond oxygen atom insertion reaction proceeded smoothly in the presence of a photoredox catalyst (2.0 mol%), DIPEA (1.5 equiv) and Na3PO4.12H2O (1.0 equiv) in CH3CN at 35 °C, upon exposure to a 90 W white LED for 24 h. Further experiments revealed that the photoredox catalyst was not essential for this transformation (Please see Supplementary Table 1 for more details). Subsequent comprehensive optimization led to the identification of standard conditions that provided a 63% isolated yield of the desired product (Table 1, entry 1). DIPEA proved crucial for this reaction, as there was no reaction in its absence (entry 2). We speculated that DIPEA functions as a potent electron donor, while its ability to form the sulfonamide salt with TsCl is hindered by the presence of two bulky iPr groups, and an Electron-Donor-Acceptor (EDA) complex may occur between the TsCl and DIPEA (Please see the Supplementary Figs. 10 and 11 for more details)63. Besides, Other electron donors such as Et3N and DABCO showed lower efficiencies (entries 3-4). As a moderate-strength inorganic base, Na3PO4.12H2O is critical for the reaction efficiency, and the yield of 3a decreased to 35% in the absence of the base (entry 5). Other inorganic base such as NaH2PO4 and K2CO3, could be used, but they afforded lower yields (entries 6-7). Different solvents were also screened, and DCM was found to be the optimal choice (entries 8–10). Not surprisingly, a control experiment verified the necessity of light for the success of the reaction (entry 11). It is worth mentioning that thermal conditions showed lower efficiency than light in this process (entry 12).
With the optimized conditions in hand, we next studied the generality of this transformation by exploring the scope of styrenes (Fig. 2). Styrenes with variety of substituents at the para-, meta-, and ortho-position, such as alkyl-, cycloalkyl-, aryl-, ester-, aryl ether-, amide- and alkoxy groups were compatible in this transformation and gave the corresponding ether products 3a-3l in moderate to good yields (39–72%). The reaction of 2-vinylnaphthalene delivered 3 m in 43% yield. Furthermore, vinylheteroarenes substrates also performed well and produced products 3n-3p in 52–70% yields. Notably, a range of complex alkenes, such as derivatives of estrone, oxaprozin, and ibuprofen were also found to perform well yielding the corresponding products 3q-3t. Unfortunately, the reactivity of 1,1- and 1,2-disubstituted styrenes (1u, 1v) was found to be lower under these oxygenation conditions probably due to the steric effect. The presence of strong electron-withdrawing groups (1w, 1x) were not tolerated, resulting in no desired products detected. In these cases, significant decomposition of most sulfonyl chlorides occurred during the reactions.
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), DIPEA (2.0 equiv), Na3PO4.12H2O (1.0 equiv), DCM (1.0 mL/0.2 M), stirred at 35 oC under Air and irradiated by 90 W white LEDs for 48 h, Isolated yields. a 2 (0.5 mmol, 2.5 equiv), DIPEA (2.5 equiv) were used. Ts tosyl, DIPEA N, N-Diisopropylethylamine, DCM Dichloromethane, Me methyl, Boc tert-butyloxycarbonyl, Ph phenyl, Ac acetyl, t-Bu tert-butyl, Bn benzyl, Et ethyl.
Next, attention was turned to exploring the functional group tolerance of the sulfonyl chloride yielding the vinyl aryl ether products. As depicted in Fig. 2, both electron-donating and electron-withdrawing substituents at the phenyl group in benzenesulfonyl chloride were found to tolerate the reaction conditions well, giving rise to the desired products in acceptable yields (4a-o). Comparatively, benzenesulfonyl chlorides with halogen groups at the para-, meta-, and ortho- positions of the phenyl group afforded the corresponding products 4k-o in yields of 40–52%. The lower yield of the ortho-substituted product may be due to the steric effect. Naphthalene-1-sulfonyl chloride and naphthalene-2-sulfonyl chloride were converted to the desired products 4p and 4q in 43% and 51% yields, respectively. In addition, the disubstituted as well as trisubstituted phenyl groups of sulfonyl chloride also delivered the desired products in acceptable yields (4r, 4s and 4v). In particular, sulfonyl chloride containing heterocycles such as 1,4-benzodioxan and dihydrobenzofura, commonly found in medicinally relevant compounds, all performed well and gave the desired products 4t and 4u in yields of 59% and 50%. Thiophene-2-sulfonyl chloride (4w) was also competent under this protocol. Moreover, complex sulfonyl chloride was also applied in this oxygenation reaction, and potentially bioactive compound 4z was obtained in a reasonable yield.
To gain insight into the mechanism, several control experiments were extensively carried out (Fig. 3). 19F NMR titration experiments and UV-Vis spectrum (Please see the Supplementary Figs. 10 and 11 for more details) indicated weak interactions between DIPEA and sulfonyl chloride 2p occurred in solution (Fig. 3a)64. The reaction was significantly inhibited in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a radical scavenger. Furthermore, a radical clock experiment using substrate 1y formed the ring-opening product 5 in 7% yield along with 47% β-hydroxysulfone compound 5’ (Fig. 3c). These experiments suggest a radical mechanism may be involved in this reaction. Moreover, 18O-labeling experiments were conducted (Fig. 3d). When the reaction was carried out in the presence of 20.0 equiv of H218O, no 18O labeled product was detected. In contrast, the oxygenation product was obtained in 60% yield with 80% 18O-labeled [18O]-3a’ in the presence of 18O2 (the formation of 3a is probably due to the impurity of 18O2 gas), which demonstrates that the oxygen atom of the aryl ether products was derived from molecular oxygen.
a 19F NMR titration experiments. b Radical trapping experiment. c Radical clock experiment. d 18O-Labeling experiments. Ts tosyl, DIPEA N,N-Diisopropylethylamin, Me methyl, TEMPO 2,2,6,6-tetramethyl-1-piperinedinyloxy.
We also performed several further transformations to demonstrate the synthetic application of the vinyl aryl ether products in forming useful molecular scaffolds (Fig. 4). For instance, enamine 6, a high-valued synthetic block, can be readily prepared in high yield using vinyl aryl ether 3a and pyrrolidine as the starting material. Moreover, thioether 7 was constructed in 76% yield by a simple Michael addition reaction of benzenemethanethiol with vinyl sulfones 3a. Radical substitution of 3a with silicon reagent in the presence of AIBN could afford the product 8 in 56% yield. In addition, the Ts group can be readily removed by treating with magnesium in MeOH to give the desired product 9a-9c in moderate to good yields.
Ts tosyl, Ph phenyl, Me methyl, Boc tert-butyloxycarbonyl, AIBN azobisisobutyronitrile, (TMS)3SiH tris(trimethylsilyl)silane, Bn benzyl.
Although the mechanism, including the photoexcitation process, is not entirely clear yet, a potential mechanism is outlined in Fig. 5 based on mechanistic studies and literature reports63,65,66. Photoexcitation or thermally activation of EDA complex generates sulfonyl radical I. The subsequent radical addition of I to 4-methylstyrene 2a produces the secondary alkyl radical II, which could be trapped by an oxygen molecule to form peroxyl radical III. Radical cross-coupling of peroxyl radical III with radical II yields intermediate IV. Alternatively, the intermediate IV could also be generated by the homocoupling of III followed by the release of dioxygen. Then, the O-O bond homolysis of the species IV produces radical V, which undergoes concerted [1,2]-aryl shift through a spiro-cyclohexadienyl radical VI67,68,69, forming the more stable phenoxymethyl radical intermediate VII. Ultimately, a Cl-atom transfer from 2a to radical intermediate VII regenerates the sulfonyl radical I, delivering the desired product 3a after β-H elimination of VIII.
Ts tosyl, DIPEA N,N-Diisopropylethylamin, Me methyl.
Discussion
In summary, we have developed an efficient method for the skeletal editing of styrenes, achieving oxygen atom insertion into the Ar-C(sp2) σ-bond and facilitating the creation of corresponding aryl ether scaffolds under mild reaction conditions. The versatility of this reaction is evident in its tolerance towards a diverse range of functional groups, making it adaptable for late-stage modifications of complex molecules. Preliminary mechanistic studies indicate that a radical-induced 1,2-aryl migration is key to the success of this process. This strategy not only expands the synthetic toolbox but also may promote the development of transformations of alkenes through C-C σ-bond cleavage.
Methods
General procedure for direct oxygenation of alkenes
A 25 mL schlenk tube was equipped with a rubber septum and magnetic stir bar and was charged with benzenesulfonyl chloride derivatives 2 (0.4 mmol, 2.0 equiv or 0.5 mmol, 2.5 equiv), Na3PO4.12H2O (0.2 mmol, 1.0 equiv). Then alkenes 1 (0.2 mmol, 1.0 equiv), DIPEA (0.4 mmol, 2.0 equiv or 0.5 mmol, 2.5 equiv) and DCM (1.0 mL, 0.20 M) were added with syringe. The mixture was stirred and irradiated by a 90 W white LED from 6 cm distance at ambient temperature for a specific time (24 h–48 h). After the reaction was complete (as judged by TLC analysis), the mixture was poured into a separatory funnel containing 10 mL H2O and 10 mL DCM. The layer was separated and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure after filtration. The crude product was purified by flash chromatography on silica gel to afford the desired product 3 or 4. For complete experimental details, including Photochemical instrumentation, related detection, procedures and full characterization (1H and 13C NMR, HRMS spectrometry) of all new compounds, see Supplementary Information.
Data availability
Supplementary information and chemical compound information accompany this paper at www.nature.com/ncomms. The data supporting the results of this work are included in this paper or in the Supplementary Information and are also available upon request from the corresponding author. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Center, under deposition numbers CCDC 2330916 (4y). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
The authors acknowledge the National Key R&D Program of China (No. 2021YFA1501700 to N. Jiao), the NSFC (Nos. 22293014 to N. Jiao, 22131002 to N. Jiao, 22161142019 to N. Jiao, 21901010 to Q. Qin), the Natural Science Foundation of Shandong Province (ZR2023MB071 to Q. Qin, ZR2021MC022 to S. Hao), the Tencent Foundation and the Doctorial Fund of Qingdao Agriculture University (665-1120030 to Q. Qin), the New Cornerstone Science Foundation through the New Cornerstone Investigator Program (to N. Jiao) and the XPLORER PRIZE (to N. Jiao) for financial support. We also thank Shouyun Yu from Nanjing University and Hua Yang from Central South University for their helpful discussions.
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Q.Q. and N.J. conceived and designed the experiments; Q.Q. and L.Z. carried out most of experiments; Q.Q., L.Z., J.W., X.Q., S.H., X.A., and N.J. analyzed data; Q.Q. and N.J. wrote the paper; N.J. directed the project.
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Qin, Q., Zhang, L., Wei, J. et al. Direct oxygen insertion into C-C bond of styrenes with air. Nat Commun 15, 9015 (2024). https://doi.org/10.1038/s41467-024-53266-6
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DOI: https://doi.org/10.1038/s41467-024-53266-6
