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Communication

Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones

1
College of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252059, China
2
Institute of Translation Medicine, Shanghai University, Shanghai 200444, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(9), 1971; https://doi.org/10.3390/molecules29091971
Submission received: 3 February 2024 / Revised: 14 April 2024 / Accepted: 22 April 2024 / Published: 25 April 2024

Abstract

:
A novel and efficient method for functionalizing organosulfones has been established, utilizing a visible-light-driven intermolecular radical cascade cyclization of α-allyl-β-ketosulfones. This process employs fac-Ir(ppy)3 as the photoredox catalyst and α-carbonyl alkyl bromide as the oxidizing agent. Via this approach, the substrates experience intermolecular addition of α-carbonyl alkyl radicals to the alkene bonds, initiating a sequence of C-C bond formations that culminate in the production of organosulfone derivatives. Notably, this technique features gentle reaction conditions and an exceptional compatibility with a wide array of functional groups, making it a versatile and valuable addition to the field of organic synthesis.

Graphical Abstract

1. Introduction

Organosulfones, exemplified by compounds such as Adociaquinones and Boehringer Ingelheim, serve as versatile components in pharmaceutical molecules, finely modulating drug metabolism and biotransformation, and have been extensively utilized in clinical trials [1,2,3,4,5]. Notably, functionalized organosulfones exhibited diverse reactivity at α-methylene/arene positions and facile sulfonyl group removal, enabling their valuable role in synthesizing biologically active compounds, pharmaceuticals, intermediates, and natural products [6,7].
More pioneering efforts have been devoted to developing useful methods for modifying organosulfones [8,9]. Among the functionalized skeletons featuring a distinctive sulfonyl group, α-ally-β-ketosulfones play a vital role as essential precursors in various organic transformations [10,11], adeptly enabling the functionalization of double bonds (Figure 1). (i) Double bond cyclization [12,13,14]: Numerous cyclization methods of α-ally-β-ketosulfones have been reported, such as In(OTf)3-catalyzed intramolecular hydroarylation of α-phenylallyl β-ketosulfones [15], Bi(OTf)3-mediated cycloisomerization of γ-alkynyl arylketones [16], and PdCl2/CuCl2/NH4OAc mediated the domino aerobic Wacker-type aminocyclization of α-allyl-β-ketosulfones [17]. (ii) Exo-olefin isomerization: In 2015, a novel Bi(OTf)3-mediated stereoselective exo-olefin isomerization of α-benzoyl-β-styrylsulfones in MeNO2 was developed to synthesis α-benzoyl α-cinnamylsulfones [18]. (iii) Aromatization following sulfonation: For instance, Bi(OTf)3-mediated intramolecular carbonyl allylation of β-ketosulfones has been reported, facilitating the synthesis of substituted benzenes. Additionally, the intermolecular Michael−aldol reaction of β-keto sulfones was employed for preparing substituted aryl amines [19].
Compared to metal catalysis, photocatalysis has attracted widespread attention due to its advantages of being environmentally friendly, green, and operating under mild reaction conditions [20,21]. Recently, visible-light-promoted radical cascade reaction of olefins has undoubtedly gained significant momentum [22,23]. In 2021, Tokyuyama used α-bromo-β-keto esters to accomplish the mild photoredox-catalyzed cyclopropanation of alkenes in an aqueous medium [24]. In addition, intermolecular organophotocatalytic cyclopropannation of unactivated olefins with α-bromomalonates was reported, displaying broad functional group tolerance and furnishing highly substituted cyclopropanes [25]. After further comparison of reports from the literature, we reported a novel visible-light-driven intermolecular radical cascade reaction of α-allyl-β-ketosulfones in the presence of α-carbonyl alkyl bromide as the oxidant for investigating valuable functionalized organosulfones (Figure 1B).

2. Results and Discussion

The optimization of reaction conditions involved exposing a blend of α-allyl-β-ketosulfones, α-bromo diethyl malonate 2a, base, and photocatalyst to blue LED irradiation, with the reaction taking place in the presence of N2 as the atmosphere (Table 1). In our initial exploration of radical addition reactions, we employed α-allyl-β-ketosulfones (1a) as the substrate, alongside 2,6-lutidine as the base and fac-Ir(ppy)3 as the photocatalyst, with all experiments conducted in a DMF solvent. Encouragingly, the desired ternary ring product 3a was obtained in 16% isolated yield (entry 1); meanwhile, 3a′ was observed as a byproduct. Subsequent screening of diverse solvents confirmed chlorobenzene as the optimal choice, such as 1,4-dioxane, trichloromethane, DMSO, toluene, acetone, and o-dichlorobenzene (entries 2–8). Further experimentation focusing on the base confirmed 2,6-lutidine as the most effective medium for this transformation (entries 9–13). Notably, additional added LiBF4 gave 3a in enhanced yield (36%) (entries 14–15) [22]. Intriguingly, the attempt to increase the amount of base boosted the yield, use of 5.0 equiv. 2,6-lutidine afforded 3a in the higher yield of 48% (entries 16–18). And the reaction exhibited greater efficacy when carried out in an inert gas environment, in contrast to the outcomes observed under ambient air conditions (entry 19). Remarkably, control experiments provided solid evidence supporting the crucial role of either visible light or the photocatalyst in facilitating the desired transformation (entries 20–21).
After obtaining the optimized reaction conditions, we proceeded to investigate the range of α-allyl-β-ketosulfones 1. As shown in Scheme 1, a diverse set of α-allyl-β-ketosulfones 1, spanning a wide range of structural variations, underwent facile transformation to afford the desired products 3. First, the efficiency of the reaction is significantly influenced by the substitution effect on the Ar2 group of skeleton 1. In cases where Ar2 is substituted with electron-donating groups like tert-butyl and methoxyl, the yield of product 3b3c (51–53%) remained unaffected. Nevertheless, the skeleton 1 resulted in the synthesis of the target product (3d), achieving a yield of 21%. Regarding the α-allyl-β-ketosulfone (1e1g), it was noted that their reactivity was decreased compared with the para-substituted counterparts. Subsquently, altering the Ar1 group to incorporate various substituents proved to be compatible. A series of α-allyl-β-ketosulfones 1 along with 4-MeOC6H4 substituents on ring Ar2, such as 4-F (1h) and 4-Cl (1i), 4-methyl (1j), 4-methoxy (1k), 3-methoxy (1l), and 2-methoxy (1m) substituents on ring Ar1 were all employed as the substrates. The result could be attributed to the electron-withdrawing nature of the substituents on Ar2, which reduces its reactivity towards oxidation by the catalyst, consequently impacting the formation of the carbocation. The results revealed strong electron-donating groups significantly contributed to improving the reaction’s efficiency. Specifically, the targeted product 3k, featuring two MeO- groups, was successfully obtained in up to 84% yield.
During the optimization of the ternary ring formation process, we unexpectedly observed the hexacyclic product 4a. After this, by optimizing the reaction conditions specifically for the synthesis of 4a, we achieved a pleasing yield of 67% (See SI, Table S1). Furthermore, it is worth noting that the product 4a yield remained positive even when the reaction was scaled up to a gram level (64% yield). Having obtained the optimized conditions, we conducted a comprehensive exploration of the substrate scope for this transformation, as summarized in Table 2. The Ar2 group with diverse substitutes, such as 4-tBu (1b), 4-MeO (1c), 4-Br (1n), Ph (1g), 2-MeC6H4- (1o), or 3-MeC6H4- (1p), proceeded cyclization reaction smoothly with moderate efficiency (48–43%, respectively, 4b4g). Notably, the reaction favored electron-donating substituents and exhibited a preference for ortho-substitution over meta- and para-substitution. Following that, we assessed the effect of various substituents on the Ar1 group (4h4j). The findings suggested that electron-donating groups were more advantageous for this reaction as opposed to electron-withdrawing groups. Then, a range of α-allyl-β-ketosulfones bearing varied substituents could undergo a remarkably efficient cyclization reaction, leading to the formation of the desired hexacyclic products (4k4q) with acceptable to moderate yields.
Finally, to expand the applicability of this protocol, we turn our attention to the scope of bromide 2. As described in Scheme 2, α-bromoalkyl ester 2b and 2c proved to be suitable reaction partners, yielding the corresponding products 5ab5ac in 45–47% isolated yields. Regrettably, the application of α-bromoalkyl esters 2d2e did not yield favorable results in this transformation, indicating their unsuitability for the process. Then, we redirected our focus towards exploring the viability of 2-bromoacetophenones in this transformation. To our delight, a broad range of 2-bromoacetophenones 5af5al, featuring with electron-donating or electron-withdrawing substituents at the ortho/meta/para-positions of the benzene ring, all proved to be highly capable partners in successfully achieving this transformation. In this case of 2-(bromoacetyl)thiophene 2m, the cyclization product 5am was isolated in 42% yield. As anticipated, this transformation was effectively extended to aliphatic bromide 2n, yielding the desired cyclization product 5an.
Based on the afore mentioned result, a plausible mechanism was postulated and detailed in Scheme 3 [26,27]. Upon visible light irradiation, the photocatalyst was energized to *fac-[IrIII(ppy)3], which underwent rapid reduction via α-bromo diethyl malonate 2a to yield the corresponding radical specie A. Subsequent intermolecular addition to the C-C double bond of compound 1 generated the radical intermediate B, followed by oxidation by fac-[IrIV(ppy)3] to yield the cationic intermediate C. Under certain reaction conditions, using 2,6-lutidine as a base and chlorobenzene as the solvent, intermediate C underwent an efficient intramolecular cyclization process, leading to the synthesis of the tricyclic compound 3. On the other hand, when employing potassium dihydrogen phosphate (K2HPO4) as the base and dimethylformamide (DMF) as the solvent, intermediate B directly underwent a radical intramolecular cyclization to give the stable intermediate D. Intermediate D was oxidized by the photocatalyst IrIV to produce cationic intermediate E, following regeneration of the photocatalyst. Finally, the intermediate E favored the loss of a proton on aromatic ring Ar2 to form the corresponding hexacyclic product 4.

3. Materials and Methods

3.1. General Information

Unless otherwise noted, all reactions were run under a nitrogen atmosphere and were monitored using TLC and visualized using a UV lamp (254 nm)/or via treatment with a solution of 10 g phosphomolybdic acid and 100 mL EtOH followed by heating. All reagents were used as received from commercial sources without further purification. Compounds 2a2n were purchased from Aladdin Reagent Co. (Shanghai, China). Silica gel (200–300 mesh) and silica gel GF254 (10–40 μm) were used for column chromatography (CC) and to prepare thin-layer chromatography (PTLC), respectively. Solvents were dried and purified according to the procedure from “Purification of Laboratory Chemicals book”. 1H NMR and 13C NMR spectra were recorded in CDCl3 on a Varian 500 MHz instrument. Chemical shifts were denoted in ppm (δ) and calibrated using residual undeuterated solvent (CDCl3 (7.26 ppm), or tetramethylsilane (0.00 ppm)) as internal reference for 1H NMR and the deuterated solvent (CDCl3 (77.00 ppm), or tetramethylsilane (0.00 ppm)) as internal standard for 13C NMR. The following abbreviations were used to denote the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, td = triple doublet, dt = double triplet, m = multiplet. The MS data were obtained using the ESI technique and the relative intensity (%) is given in brackets. High-resolution mass spectral analysis (HRMS) data were measured using a Waters G2-xs Q-TOF mass spectrometer by means of the ESI technique.

3.2. General Procedure for Preparation of Substrates

Substrates 1a [17,28], 1b [28], 1cd [17], 1g [28], 1p [28], 1qr [17] are known compounds and the analytical data are consistent with the previous literature.
2-((3-Methoxyphenyl)sulfonyl)-1-phenylpent-4-en-1-one (1e): Colorless solid; mp = 95.6–96.1 °C; 1H NMR (500 MHz, CDCl3): δH 7.91 (d, J = 9.0 Hz, 2 H), 7.58 (t, J = 7.7 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 7.23 (s, 1 H), 7.15–7.13 (m, 1 H), 5.63–5.55 (m, 1 H), 5.13 (t, J = 7.3 Hz, 1 H), 5.05 (dd, J = 17.0, 1.0 Hz, 1 H), 4.98 (dd, J = 10.0, 1.0 Hz, 1 H), 3.80 (s, 3 H), 2.88–2.84 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 191.6, 159.7, 137.4, 137.0, 134.0, 131.8, 129.9, 128.9, 128.7, 121.8, 120.8, 119.0, 114.1, 69.1, 55.6, 32.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H18NaO4S+, 353.0818, found 353.0801.
2-((2-Methoxyphenyl)sulfonyl)-1-phenylpent-4-en-1-one (1f): Colorless solid; mp = 96.8–97.2 °C; 1H NMR (500 MHz, CDCl3): δH 7.88 (dd, J = 8.3, 1.3 Hz, 2 H), 7.85 (dd, J = 8.3, 1.3 Hz, 1 H), 7.56–7.50 (m, 2 H), 7.41 (t, J = 7.7 Hz, 2 H), 7.04 (td, J = 7.7, 1.0 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 5.66–5.58 (m, 1 H), 5.53 (dd, J = 10.7, 3.7 Hz, 1 H), 5.06 (dd, J = 17.0, 1.0 Hz, 1 H), 4.97 (dd, J = 10.0, 1.0 Hz, 1 H), 3.88 (s, 3 H), 3.16–3.09 (m, 1 H), 2.78–2.74 (m, 1 H); 13C NMR (126 MHz, CDCl3): δc 191.5, 157.3, 137.4, 136.1, 133.6, 132.4, 131.6, 128.7, 128.5, 125.8, 120.8, 118.8, 112.2, 67.4, 56.1, 31.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H18NaO4S+, 353.0818, found 353.0804.
1-(4-Fluorophenyl)-2-((4-methoxyphenyl)sulfonyl)pent-4-en-1-one (1h): Colorless solid; mp = 117.5–118.5 °C; 1H NMR (500 MHz, CDCl3): δH 8.00 (dd, J = 8.7, 5.3 Hz, 2 H), 7.67 (d, J = 8.7 Hz, 2 H), 7.15 (t, J = 8.7 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 5.61–5.52 (m, 1 H), 5.06 (dd, J = 11.0, 3.5 Hz, 1 H), 5.04–4.96 (m, 2 H), 3.88 (s, 3 H), 2.85–2.71 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 190.5, 166.2 (d, J = 257.5 Hz), 164.3, 133.6 (d, J = 3.2 Hz), 132.0, 131.9 (d, J = 2.5 Hz), 131.8, 127.4, 119.0, 115.9 (d, J = 22.2 Hz), 114.2, 69.4, 55.7, 32.4; 19F NMR (470 MHz, CDCl3): δF −103.2 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17FNaO4S+, 371.0724, found 371.0735.
1-(4-Bromophenyl)-2-((4-methoxyphenyl)sulfonyl)pent-4-en-1-one (1i): Colorless solid; mp = 115.4–116.1 °C; 1H NMR (500 MHz, CDCl3): δH 7.82 (d, J = 8.7 Hz, 2 H), 7.66 (d, J = 8.7 Hz, 2 H), 7.62 (d, J = 8.7 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 5.60–5.52 (m, 1 H), 5.05–5.00 (m, 2 H), 4.97 (d, J = 10.0 Hz, 1 H), 3.88 (s, 3 H), 2.85–2.71 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 191.3, 164.4, 135.9, 132.1, 132.0, 131.8, 130.5, 129.5, 127.3, 119.1, 114.2, 69.5, 55.7, 32.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17BrNaO4S+, 430.9923, found 430.9924.
2-((4-Methoxyphenyl)sulfonyl)-1-(p-tolyl)pent-4-en-1-one (1j): Colorless solid; mp = 110.1–110.9 °C; 1H NMR (500 MHz, CDCl3): δH 7.85 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 2 H), 5.61–5.53 (m, 1 H), 5.09 (dd, J = 11.0, 3.5 Hz, 1 H), 5.02 (dd, J = 17.0, 1.3 Hz, 1 H), 4.95 (dd, J = 10.3, 1.3 Hz, 1 H), 3.86 (s, 3 H), 2.85–2.72 (m, 2 H), 2.41 (s, 3 H); 13C NMR (126 MHz, CDCl3): δc 191.5, 164.2, 145.1, 134.7, 132.0, 132.0, 129.4, 129.1, 127.6, 118.7, 114.0, 69.1, 55.6, 32.4, 21.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C19H20NaO4S+, 367.0975, found 355.0788.
1-(4-Methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)pent-4-en-1-one (1k): Colorless solid; mp = 75.1–75.8 °C; 1H NMR (500 MHz, CDCl3): δH 7.94 (d, J = 9.0 Hz, 2 H), 7.67 (d, J = 9.0 Hz, 2 H), 6.95 (d, J = 9.0 Hz, 2 H), 6.93 (d, J = 9.0 Hz, 2 H), 5.61–5.53 (m, 1 H), 5.07–5.01 (m, 2 H), 4.95 (dd, J = 10.0, 1.0 Hz, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.84–2.72 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 190.1, 164.2, 164.1, 132.1, 131.9, 131.5, 130.2, 127.6, 118.6, 114.0, 113.9, 69.0, 55.6, 55.5, 32.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C19H20NaO5S+, 383.0924, found 383.0907.
1-(3-Methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)pent-4-en-1-one (1l): Colorless solid; mp = 103.2–104.1 °C; 1H NMR (500 MHz, CDCl3): δH 7.69 (d, J = 9.0 Hz, 2 H), 7.52 (d, J = 7.7 Hz, 1 H), 7.42 (t, J = 2.0 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.13 (dd, J = 7.7, 2.7 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 2 H), 5.62–5.54 (m, 1 H), 5.09 (dd, J = 11.0, 3.5 Hz, 1 H), 5.03 (dd, J = 17.0, 1.3 Hz, 1 H), 4.97 (dd, J = 10.0, 1.3 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 2.86–2.73 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 192.0, 164.2, 159.8, 138.4, 132.0, 131.9, 129.7, 127.6, 121.7, 120.5, 118.9, 114.1, 112.9, 69.4, 55.6, 55.4, 32.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C19H20NaO5S+, 383.0924, found 383.0917.
1-(2-Methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)pent-4-en-1-one (1m): Colorless solid; mp = 103.6–104.2 °C; 1H NMR (500 MHz, CDCl3): δH 7.67 (d, J = 9.0 Hz, 2 H), 7.59 (dd, J = 7.7, 1.7 Hz, 1 H), 7.45 (td, J = 7.7, 1.7 Hz, 1 H), 6.97 (t, J = 8.0 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.89 (d, J = 8.0 Hz, 1 H), 5.75–5.67 (m, 1 H), 5.64 (dd, J = 9.0, 5.5 Hz, 1 H), 5.08 (dd, J = 17.0, 1.5 Hz, 1 H), 5.00 (dd, J = 10.3, 1.5 Hz, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 2.83–2.77 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 193.6, 163.9, 158.5, 134.7, 132.9, 131.7, 131.2, 128.6, 127.7, 120.9, 118.0, 113.8, 111.7, 72.9, 55.6, 55.5, 32.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C19H20NaO5S+, 383.0924, found 383.0913.
2-((4-Bromophenyl)sulfonyl)-1-phenylpent-4-en-1-one (1n): Colorless solid; mp = 104.3–105.4 °C; 1H NMR (500 MHz, CDCl3): δH 7.93 (d, J = 8.7 Hz, 2 H), 7.66–7.59 (m, 5 H), 7.47 (t, J = 8.7 Hz, 2 H), 5.61–5.53 (m, 1 H), 5.15 (dd, J = 11.0, 3.5 Hz, 1 H), 5.04 (d, J = 17.0 Hz, 1 H), 4.98 (d, J = 10.0 Hz, 1 H), 2.87–2.72 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 191.8, 136.9, 135.1, 134.1, 132.2, 131.5, 131.3, 129.9, 128.9, 128.8, 119.2, 69.1, 32.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C17H15BrNaO3S+, 400.9817, found 400.9818.
1-Phenyl-2-(o-tolylsulfonyl)pent-4-en-1-one (1o): Colorless solid; mp = 81.2–81.9 °C; 1H NMR (500 MHz, CDCl3): δH 7.82 (t, J = 7.3 Hz, 3 H), 7.54 (t, J = 7.3 Hz, 1 H), 7.45–7.38 (m, 3 H), 7.31–7.27 (m, 1 H), 7.21 (d, J = 7.3 Hz, 1 H), 5.65–5.55 (m, 1 H), 5.13 (dd, J = 11.0, 3.5 Hz, 1 H), 5.07 (d, J = 17.0 Hz, 1 H), 4.99 (d, J = 10.0 Hz, 1 H), 3.05–2.99 (m, 1 H), 2.88–2.83 (m, 1 H), 2.61 (s, 3 H); 13C NMR (126 MHz, CDCl3): δc 191.4, 139.1, 137.0, 134.2, 133.8, 132.8, 132.0, 131.8, 129.0, 128.6, 128.6, 126.5, 119.1, 69.2, 31.5, 20.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H18NaO3S+, 337.0869, found 337.0851.
1-(4-Bromophenyl)-2-tosylpent-4-en-1-one (1s): Colorless solid; mp = 109.3–110.2 °C; 1H NMR (500 MHz, CDCl3): δH 7.81 (d, J = 8.3 Hz, 2 H), 7.63–7.61 (m, 4 H), 7.32 (d, J = 8.3 Hz, 2 H), 5.60–5.52 (m, 1 H), 5.05–5.00 (m, 2 H), 4.97 (d, J = 10.5 Hz, 2 H), 2.86–2.72 (m, 2 H), 2.45 (s, 3 H); 13C NMR (126 MHz, CDCl3): δc 191.1, 145.7, 135.9, 133.0, 132.1, 131.8, 130.5, 129.8, 129.6, 129.5, 119.1, 69.4, 32.3, 21.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17BrNaO3S+, 414.9974, found 414.9963.
2-((4-Fluorophenyl)sulfonyl)-1-(p-tolyl)pent-4-en-1-one (1t): Colorless solid; mp = 129.4–130.1 °C; 1H NMR (500 MHz, CDCl3): δH 7.84 (d, J = 8.5 Hz, 2 H), 7.78 (dd, J = 8.5, 5.0 Hz, 2 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.19 (t, J = 8.5 Hz, 2 H), 5.62–5.53 (m, 1 H), 5.11 (dd, J = 10.7, 3.7 Hz, 1 H), 5.04 (dd, J = 11.3, 1.3 Hz, 1 H), 4.98 (dd, J = 11.3, 1.3 Hz, 1 H), 2.87–2.71 (m, 2 H), 2.43 (s, 3 H); 13C NMR (126 MHz, CDCl3): δc 191.4, 166.2 (d, J = 257.8 Hz), 145.4, 134.5, 132.8 (d, J = 9.8 Hz), 132.2 (d, J = 3.2 Hz), 131.7, 129.6, 129.2, 119.1, 116.2 (d, J = 22.7 Hz), 69.1, 32.5, 21.7; 19F NMR (470 MHz, CDCl3): δF −102.4 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17FNaO3S+, 355.0775, found 355.0778.
2-((4-Fluorophenyl)sulfonyl)-1-(4-methoxyphenyl)pent-4-en-1-one (1u): Colorless solid; mp = 92.4–93.3 °C; 1H NMR (500 MHz, CDCl3): δH 7.94 (d, J = 9.0 Hz, 2 H), 7.78 (dd, J = 8.7, 5.0 Hz, 2 H), 7.20 (t, J = 8.7 Hz, 2 H), 6.95 (d, J = 9.0 Hz, 2 H), 5.61–5.53 (m, 1 H), 5.08 (dd, J = 11.0, 3.5 Hz, 1 H), 5.04 (dd, J = 17.0, 1.3 Hz, 1 H), 4.98 (dd, J = 11.0, 1.3 Hz, 1 H), 3.89 (s, 3 H), 2.86–2.70 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 189.9, 166.2 (d, J = 257.8 Hz), 164.5, 132.8 (d, J = 9.7 Hz), 132.2 (d, J = 3.2 Hz), 131.8, 131.5, 130.0, 119.0, 116.2 (d, J = 22.8 Hz), 114.1, 69.0, 55.6, 32.4; 19F NMR (470 MHz, CDCl3): δF −102.5 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17FNaO4S+, 371.0724, found 371.0730.
2-((4-Bromophenyl)sulfonyl)-1-(4-methoxyphenyl)pent-4-en-1-one (1v): Colorless solid; mp = 102.4–103.2 °C; 1H NMR (500 MHz, CDCl3): δH 7.93 (d, J = 8.7 Hz, 2 H), 7.65 (d, J = 8.7 Hz, 2 H), 7.61 (d, J = 8.7 Hz, 2 H), 6.94 (d, J = 8.7 Hz, 2 H), 5.61–5.53 (m, 1 H), 5.09–5.03 (m, 2 H), 4.98 (d, J = 10.0 Hz, 1 H), 3.88 (s, 3 H), 2.85–2.71 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 189.7, 164.5, 135.2, 132.2, 131.8, 131.5, 131.3, 130.0, 129.8, 119.0, 114.1, 69.0, 55.6, 32.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17BrNaO4S+, 430.9923, found 430.9934.
2-((4-Fluorophenyl)sulfonyl)-1-(3-methoxyphenyl)pent-4-en-1-one (1w): Colorless solid; mp = 63.5–64.1 °C; 1H NMR (500 MHz, CDCl3): δH 7.79 (dd, J = 8.3, 5.0 Hz, 2 H), 7.51 (d, J = 8.3 Hz, 1 H), 7.42 (s, 1 H), 7.39 (t, J = 8.3 Hz, 1 H), 7.20 (t, J = 8.3 Hz, 2 H), 7.15 (dd, J = 8.3, 1.7 Hz, 1 H), 5.62–5.54 (m, 1 H), 5.11 (dd, J = 11.0, 3.5 Hz, 1 H), 5.05 (dd, J = 17.0, 1.0 Hz, 1 H), 4.99 (d, J = 10.0 Hz, 1 H), 3.86 (s, 3 H), 2.88–2.72 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 191.8, 166.3 (d, J = 257.9 Hz), 160.0, 138.3, 132.8 (d, J = 9.7 Hz), 132.3, 131.6, 129.8, 121.7, 120.7, 119.2, 116.2 (d, J = 22.6 Hz), 113.1, 69.5, 55.5, 32.6; 19F NMR (470 MHz, CDCl3): δF −102.3 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17FNaO4S+, 371.0724, found 371.0728.
2-((4-Fluorophenyl)sulfonyl)-1-(2-methoxyphenyl)pent-4-en-1-one (1x): Colorless solid; mp = 80.2–81.3 °C; 1H NMR (500 MHz, CDCl3): δH 7.77 (dd, J = 8.7, 5.0 Hz, 2 H), 7.60 (dd, J = 7.7, 1.7 Hz, 1 H), 7.48 (td, J = 7.7, 1.7 Hz, 1 H), 7.14 (t, J = 8.7 Hz, 2 H), 6.99 (t, J = 7.7 Hz, 1 H), 6.90 (d, J = 7.7 Hz, 1 H), 5.75–5.65 (m, 2 H), 5.09 (dd, J = 17.0, 1.5 Hz, 1 H), 5.02 (d, J = 10.0 Hz, 1 H), 3.89 (s, 3 H), 2.85–2.76 (m, 2 H); 13C NMR (126 MHz, CDCl3): δc 193.2, 165.9 (d, J = 257.9 Hz), 158.6, 135.0, 133.3, 132.6, 132.5 (d, J = 9.7 Hz), 131.3, 127.5, 121.1, 118.3, 115.9 (d, J = 22.8 Hz), 111.9, 73.0, 55.6, 32.2; 19F NMR (470 MHz, CDCl3): δF −103.1 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C18H17FNaO4S+, 371.0724, found 371.0727.

3.3. General Procedure for the Synthesis of Compound 3a

A 25 mL Schlenk flask was equipped with a magnetic stir bar and was charged with compounds 1a (0.2 mmol), 2 (0.4 mmol), 2,6-lutidine (107.0 mg, 1.0 mmol), LiBF4 (37.5 mg, 0.4 mmol), chlorobenzene (0.5 mL), and fac-Ir(ppy)3 (6.6 mg, 0.005 mmol). The Schlenk flask was evacuated and backfilled with N2 three times under −78 °C. The mixture was irradiated with blue LEDs for 53 h (monitored using TLC). After the reaction was completed, the reaction mixture was purified using PTLC (petroleum ether/EtOAc) to obtain the desired product 3a.

3.4. General Procedure for Gram Scale Reaction of Compound 4a

A 100 mL Schlenk flask was equipped with magnetic stir bar and was charged with compounds 1a (1.256 g, 4.0 mmol, 1.0 equiv.), 2a (3.824g, 8.0 mmol, 2.0 equiv.), K2HPO4 (2.784 g, 8.0 mmol, 2.0 equiv.), dry DMF (40 mL), and fac-Ir(ppy)3 (132 mg, 0.2 mmol). The Schlenk flask was evacuated and backfilled with N2 three times under −78 °C. The mixture was irradiated with blue LEDs for 24 h (monitored using TLC). After the reaction was completed, the reaction mixture was quenched with water (50 mL) and was extracted with EtOAc (50 mL × 4). The organic layer was combined, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel (petroleum ether/EtOAc) to obtain the desired product 4a.
Diethyl 2-(3-oxo-3-phenyl-2-tosylpropyl)cyclopropane-1,1-dicarboxylate (3a): Colorless oil (45.3 mg, 48% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.96 (d, J = 7.7 Hz, 2.0 H), 7.59 (t, J = 7.7 Hz, 3.0 H), 7.49–7.44 (m, 2.0 H), 7.28–7.27 (m, 2.0 H), 5.34 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.19 (dd, J = 8.7, 4.7 Hz, 0.33 H), 4.30–3.97 (m, 4.0 H), 2.41 (s, 3.0 H), 2.39–2.33 (m, 0.67 H), 2.30–2.24 (m, 0.33 H), 2.00–1.94 (m, 1.0 H), 1.87–1.80 (m, 0.33 H), 1.64–1.57 (m, 0.67 H), 1.36 (t, J = 6.7 Hz, 2.0 H), 1.33–1.27 (m, 2.0 H), 1.20 (q, J = 6.7 Hz, 2.0 H), 1.10 (t, J = 6.7 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.5, 192.0, 169.4, 169.4, 167.4, 167.4, 145.5, 145.4, 137.2, 136.7, 134.0, 134.0, 133.4, 133.2, 129.6, 129.5, 129.1, 128.9, 128.7, 69.3, 68.5, 61.9, 61.6, 61.6, 61.5, 34.4, 33.9, 28.1, 27.6, 24.7, 24.4, 21.6, 20.5, 20.1, 14.1, 14.0, 13.9, 13.8; IR: ῡ = 1725, 1678, 1595, 1447, 1147, 748 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H28NaO7S+, 495.1448, found 495.1439.
Diethyl 2-(2-bromo-5-oxo-5-phenyl-4-tosylpentyl)malonate (3a′): Colorless oil. 1H NMR (500 MHz, CDCl3): δH 7.97 (d, J = 7.5 Hz, 2.0 H), 7.62–7.57 (m, 3.0 H), 7.46 (t, J = 7.5 Hz, 2.0 H), 7.30–7.27 (m, 2.0 H), 5.56 (dd, J = 11.3, 2.7 Hz, 0.67 H), 5.41 (t, J = 6.0 Hz, 0.33 H), 4.22–4.09 (m, 4.0 H), 3.73–3.67 (m, 1.0 H), 3.63 (dd, J = 10.0, 5.0 Hz, 0.67 H), 2.68–2.63 (m, 1.0 H), 2.56–2.43 (m, 2.0 H), 2.42 (s, 3.0 H), 2.35–2.29 (m, 0.67 H), 2.21–2.15 (m, 0.33 H), 1.27–1.23 (m, 4.33 H), 1.18 (t, J = 7.0 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 191.9, 191.3, 168.5, 168.5, 168.3, 168.1, 145.7, 145.7, 136.8, 136.3, 134.2, 134.0, 133.2, 132.9, 129.8, 129.7, 129.7, 129.5, 129.3, 129.2, 128.7, 68.8, 68.2, 61.8, 61.7, 51.2, 50.5, 50.2, 50.2, 38.1, 37.7, 37.2, 36.7, 21.7, 14.0, 13.9, 13.9; IR: ῡ = 1728, 1678, 1595, 1447, 1147, 736 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H29BrNaO7S+, 575.0710, found 575.0701.
Diethyl 2-(2-((4-(tert-butyl)phenyl)sulfonyl)-3-oxo-3-phenylpropyl)cyclopropane-1,1-dicarboxylate (3b): Colorless oil (52.4 mg, 51% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.91 (d, J = 8.0 Hz, 2.0 H), 7.64–7.60 (m, 2.0 H), 7.59–7.55 (m, 1.0 H), 7.46–7.41 (m, 4.0 H), 5.34 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.18 (dd, J = 9.0, 4.5 Hz, 0.33 H), 4.30–3.97 (m, 4.0 H), 2.46–2.40 (m, 0.67 H), 2.34–2.28 (m, 0.33 H), 2.02–1.94 (m, 1.0 H), 1.88–1.82 (m, 0.33 H), 1.65–1.59 (m, 1.0 H), 1.35 (t, J = 7.3 Hz, 2.0 H), 1.34–1.31(m, 1.67 H), 1.30 (s, 9.0 H), 1.22–1.18 (m, 2.0 H), 1.09 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.5, 192.0, 169.4, 169.4, 167.5, 167.4, 158.3, 158.2, 137.2, 136.8, 134.0, 134.0, 133.6, 133.3 129.5, 129.4, 129.0, 128.8, 128.7, 125.9, 69.2, 68.4, 61.9, 61.6, 61.5, 35.2, 34.5, 34.0, 31.0, 30.9, 27.8, 27.4, 24.8, 24.5, 20.5, 20.1, 14.1, 14.1, 14.0, 13.9; IR: ῡ = 1723, 1682, 1594, 1447, 1153, 734 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C28H34NaO7S+, 537.1917, found 537.1893.
Diethyl 2-(2-((4-methoxyphenyl)sulfonyl)-3-oxo-3-phenylpropyl)cyclopropane-1,1-dicarboxylate (3c): Colorless oil (51.8 mg, 53% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.97 (d, J = 8.0 Hz, 2.0 H), 7.65–7.59 (m, 3.0 H), 7.50–7.45 (m, 2.0 H), 6.94–6.92 (m, 2.0 H), 5.33 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.19 (dd, J = 9.0, 4.5 Hz, 0.33 H), 4.32–3.98 (m, 4.0 H), 3.85 (s, 3.0 H), 2.35–2.23 (m, 1.0 H), 1.99–1.92 (m, 1.0 H), 1.86–1.79 (m, 0.33 H), 1.63–1.57 (m, 1.0 H), 1.36 (t, J = 7.3 Hz, 2.0 H), 1.33–1.24 (m, 1.67 H), 1.20 (q, J = 7.3 Hz, 2.0 H), 1.10 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.7, 192.2, 169.4, 169.4, 167.5, 167.4, 164.2, 164.2, 137.2, 136.7, 134.1, 134.1, 131.9, 131.9, 129.2, 129.0, 128.7, 127.6, 127.4, 114.1, 69.3, 68.5, 62.0, 61.6, 61.6, 55.7, 34.4, 33.9, 28.2, 27.7, 24.7, 24.4, 20.5, 20.1, 14.1, 14.0, 14.0, 13.9; IR: ῡ = 1722, 1680, 1594, 1447, 1145, 736 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H28NaO8S+, 511.1397, found 511.1398.
Diethyl 2-(2-((4-fluorophenyl)sulfonyl)-3-oxo-3-phenylpropyl)cyclopropane-1,1-dicarboxylate (3d): Colorless oil (20.1 mg, 21% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.96 (d, J = 8.0 Hz, 2.0 H), 7.76–7.71 (m, 2.0 H), 7.64–7.60 (m, 1.0 H), 7.50–7.46 (m, 2.0 H), 7.18–7.14 (m, 2.0 H), 5.38 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.22 (dd, J = 8.7, 4.7 Hz, 0.33 H), 4.33–3.98 (m, 4.0 H), 2.41–2.32 (m, 0.67 H), 2.27–2.20 (m, 0.33 H), 2.04–1.94 (m, 1.0 H), 1.87–1.81 (m, 0.33 H), 1.65–1.60 (m, 0.67 H), 1.37 (t, J = 7.0 Hz, 2.0 H), 1.33–1.25 (m, 2.0 H), 1.21 (m, 2.0 H), 1.10 (t, J = 7.0 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.5, 192.0, 169.4, 169.3, 167.5, 167.2, 166.2 (d, J = 258.2 Hz), 137.0, 136.5, 134.3, 134.3, 132.7, 132.7, 132.6, 132.6, 132.3 (d, J = 3.2 Hz), 132.1 (d, J = 3.2 Hz), 129.1, 128.9, 128.9, 116.2 (d, J = 22.9 Hz), 69.3, 68.4, 62.1, 61.7, 61.6, 34.5, 34.0, 28.2, 27.7, 24.7, 24.3, 20.5, 20.2, 14.1, 14.1, 14.0, 13.9; 19F NMR (470 MHz, CDCl3): δF −102.1 (s) ppm; IR: ῡ = 1722, 1680, 1594, 1447, 1145, 736 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H25FNaO7S+, 499.1197, found 499.1189.
Diethyl 2-(2-((3-methoxyphenyl)sulfonyl)-3-oxo-3-phenylpropyl)cyclopropane-1,1-dicarboxylate (3e): Colorless oil (35.1 mg, 36% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.93 (d, J = 8.0 Hz, 2.0 H), 7.61–7.57 (m, 1.0 H), 7.48–7.43 (m, 2.0 H), 7.39–7.36 (m, 1.0 H), 7.33–7.31 (m, 1.0 H), 7.18 (d, J = 8.0 Hz, 1.0 H), 7.11 (d, J = 8.0 Hz, 1.0 H), 5.36 (dd, J = 11.3, 2.7 Hz, 0.67 H), 5.20 (dd, J = 9.0, 5.0 Hz, 0.33 H), 4.30–3.97 (m, 4.0 H), 3.80 (s, 2.0 H), 3.79 (s, 1.0 H), 2.47–2.41 (m, 0.67 H), 2.35–2.30 (m, 0.33 H), 2.04–1.95 (m, 1.0 H), 1.87–1.81 (m, 0.33 H), 1.63–1.58 (m, 0.67 H), 1.37–1.25 (m, 5.0 H), 1.22–1.19 (m, 2.0 H), 1.09 (t, J = 7.0 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.2, 191.7, 169.4, 169.4, 167.5, 167.4, 159.7, 137.6, 137.5, 137.1, 136.7, 134.1, 134.1, 130.0, 129.9, 129.0, 128.9, 128.7, 121.7, 121.7, 121.0, 120.8, 113.9, 113.9, 69.3, 68.4, 62.0, 61.7, 61.6, 61.6, 55.7, 55.6, 34.5, 33.9, 27.9, 27.5, 24.8, 24.4, 20.5, 20.2, 14.1, 14.0, 14.0, 13.9; IR: ῡ = 1722, 1680, 1594, 1447, 1145, 736 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H25FNaO7S+, 499.1197, found 499.1193.
Diethyl 2-(2-((2-methoxyphenyl)sulfonyl)-3-oxo-3-phenylpropyl)cyclopropane-1,1-dicarboxylate (3f): Colorless oil (27.4 mg, 28% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.93 (d, J = 8.0 Hz, 2.0 H), 7.80 (dd, J = 8.0, 1.3 Hz, 1.0 H), 7.57–7.53 (m, 1.0 H), 7.52–7.47 (m, 1.0 H), 7.42 (q, J = 8.0 Hz, 2.0 H), 7.04–6.99 (m, 1.0 H), 6.92 (d, J = 8.0 Hz, 0.33 H), 6.86 (d, J = 8.0 Hz, 0.67 H), 5.77 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.64 (dd, J = 8.0, 5.5 Hz, 0.33 H), 4.19–3.97 (m, 4.0 H), 3.93 (s, 1.0 H), 3.91 (s, 2.0 H), 2.71–2.65 (m, 0.67 H), 2.48–2.42 (m, 0.33 H), 2.04–1.99 (m, 0.33 H), 1.93–1.81 (m, 1.0 H), 1.71–1.64 (m, 0.67 H), 1.38–1.25 (m, 5.0 H), 1.20 (t, J = 7.3 Hz, 1.0 H), 1.16 (t, J = 7.3 Hz, 1.0 H), 1.09 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.3, 191.6, 169.5, 169.5, 167.4, 167.4, 157.5, 157.3, 137.6, 137.1, 136.1, 136.0, 133.7, 133.7, 131.6, 131.3, 128.9, 128.7, 128.5, 126.1, 125.7, 120.8, 120.6, 112.3, 112.1, 67.6, 66.3, 61.7, 61.6, 61.6, 61.5, 56.2, 56.1, 34.6, 33.9, 27.2, 27.0, 25.1, 24.7, 20.7, 20.3, 14.0, 14.0, 14.0, 13.9; IR: ῡ = 1722, 1680, 1594, 1447, 1145, 736 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H25FNaO7S+, 499.1197, found 499.1192.
Diethyl 2-(3-oxo-3-phenyl-2-(phenylsulfonyl)propyl)cyclopropane-1,1-dicarboxylate (3g): Colorless oil (24.8 mg, 27% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.94 (d, J = 7.5 Hz, 2.0 H), 7.72 (t, J = 7.5 Hz, 2.0 H), 7.62–7.57 (m, 2.0 H), 7.50–7.43 (m, 4.0 H), 5.37 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.21 (dd, J = 9.0, 5.0 Hz, 0.33 H), 4.29–3.98 (m, 4.0 H), 2.42–2.36 (m, 0.67 H), 2.34–2.25 (m, 0.33 H), 2.02–1.94 (m, 1.0 H), 1.86–1.80 (m, 0.33 H), 1.63–1.57 (m, 0.67 H), 1.37–1.29 (m, 4.0 H), 1.20 (q, J = 7.3 Hz, 2.0 H), 1.09 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.3, 191.9, 169.4, 169.3, 167.4, 167.4, 137.1, 136.7, 136.4, 136.3, 134.3, 134.2, 134.1, 134.1, 129.6, 129.6, 129.1, 128.9, 128.7, 69.3, 68.4, 61.9, 61.6, 61.6, 61.5, 34.4, 33.9, 28.0, 27.6, 24.7, 24.4, 20.5, 20.1, 14.1, 14.0, 13.9, 13.8; IR: ῡ = 1720, 1681, 1447, 1137, 911, 731 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H26NaO7S+, 481.1291, found 481.1272.
Diethyl 2-(3-(4-fluorophenyl)-2-((4-methoxyphenyl)sulfonyl)-3-oxopropyl)cyclopropane-1,1-dicarboxylate (3h): Colorless oil (48.6 mg, 48% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.02–8.00 (m, 2.0 H), 7.61 (t, J = 8.5 Hz, 2.0 H), 7.16–7.12 (m, 2.0 H), 6.94–6.92 (m, 2.0 H), 5.27 (dd, J = 11.5, 2.7 Hz, 0.67 H), 5.13 (dd, J = 9.0, 4.5 Hz, 0.33 H), 4.30–3.98 (m, 4.0 H), 3.85 (s, 3.0 H), 2.36–2.30 (m, 0.67 H), 2.24–2.18 (m, 0.33 H), 1.98–1.89 (m, 1.0 H), 1.84–1.78 (m, 0.33 H), 1.61–1.54 (m, 0.67 H), 1.35 (t, J = 7.3 Hz, 2.0 H), 1.32–1.24 (m, 2.0 H), 1.22–1.18 (m, 2.0 H), 1.10 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 191.0, 190.6, 169.4, 169.3, 167.4, 166.3 (d, J = 257.5 Hz), 164.3, 164.2, 133.6 (d, J = 2.8 Hz), 133.2 (d, J = 2.8 Hz), 132.0, 132.0, 131.8, 131.8, 131.8, 131.8, 127.5, 127.3, 115.9 (d, J = 22.2 Hz), 115.9 (d, J = 22.2 Hz), 114.1, 114.1, 69.4, 68.5, 62.0, 61.6, 61.6, 61.6, 55.6, 34.4, 33.9, 28.1, 27.7, 24.7, 24.3, 20.5, 20.1, 14.1, 14.0, 13.9, 13.8; 19F NMR (470 MHz, CDCl3): δF −103.0 (s) ppm; IR: ῡ = 1720, 1675, 1590, 1492, 1148, 733 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27FNaO7S+, 529.1303, found 529.1297.
Diethyl 2-(3-(4-bromophenyl)-2-((4-methoxyphenyl)sulfonyl)-3-oxopropyl)cyclopropane-1,1-dicarboxylate (3i): Colorless oil (57.8 mg, 51% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.83 (d, J = 8.5 Hz, 2.0 H), 7.63–7.59 (m, 4.0 H), 6.95–6.92 (m, 2.0 H), 5.26 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.12 (dd, J = 8.7, 4.7 Hz, 0.33 H), 4.31–3.99 (m, 4.0 H), 3.86 (s, 3.0 H), 2.39–2.31 (m, 0.67 H), 2.23–2.17 (m, 0.33 H), 2.01–1.89 (m, 1.0 H), 1.85–1.79 (m, 0.33 H), 1.59–1.54 (m, 0.67 H), 1.36 (t, J = 7.0 Hz, 2.0 H), 1.34–1.28 (m, 2.0 H), 1.23–1.19 (m, 2.0 H), 1.12 (t, J = 7.0 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 191.8, 191.3, 169.4, 169.4, 167.4, 164.4, 164.3, 135.9, 135.5, 132.1, 132.1, 131.8, 130.6, 130.4, 129.6, 127.5, 127.3, 114.2, 69.6, 68.6, 62.0, 61.7, 61.7, 61.6, 55.7, 34.4, 33.9, 28.1, 27.7, 24.7, 24.3, 20.5, 20.1, 14.1, 14.0, 14.0, 13.9; IR: ῡ = 1720, 1680, 1593, 1496, 1136, 731 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27BrNaO8S+, 589.0502, found 589.0512.
Diethyl 2-(2-((4-methoxyphenyl)sulfonyl)-3-oxo-3-(p-tolyl)propyl)cyclopropane-1,1-dicarboxylate (3j): Colorless oil (63.3 mg, 63% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.87 (d, J = 8.7 Hz, 2.0 H), 7.62 (t, J = 8.7 Hz, 2.0 H), 7.28–7.25 (m, 2.0 H), 6.94–6.91 (m, 2.0 H), 5.29 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.15 (dd, J = 9.0, 4.5 Hz, 0.33 H), 4.32–3.98 (m, 4.0 H), 3.85 (s, 3.0 H), 2.42 (s, 1.0 H), 2.41 (s, 2.0 H), 2.32–2.22 (m, 1.0 H), 1.98–1.89 (m, 1.0 H), 1.85–1.78 (m, 0.33 H), 1.62–1.57 (m, 0.67 H), 1.36 (t, J = 7.3 Hz, 2.0 H), 1.34–1.24 (m, 2.0 H), 1.23–1.18 (m, 2.0 H), 1.10 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 192.0, 191.6, 169.4, 169.4, 167.5, 167.4, 164.2, 164.1, 145.3, 145.2, 134.8, 134.3, 131.9, 129.4, 129.3, 129.1, 127.7, 127.5, 114.0, 114.0, 69.2, 68.4, 62.0, 61.6, 61.6, 61.5, 55.6, 34.4, 33.9, 28.2, 27.7, 24.7, 24.5, 21.7, 21.7, 20.5, 20.1, 14.1, 14.1, 14.0, 13.8; IR: ῡ = 1720, 1675, 1590, 1492, 1148, 733 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO8S+, 525.1554, found 525.1542.
Diethyl 2-(3-(4-methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)-3-oxopropyl)cyclopropane-1,1-dicarboxylate (3k): Colorless oil (87.1 mg, 84% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.96 (d, J = 9.3 Hz, 2.0 H), 7.62 (t, J = 9.3 Hz, 2.0 H), 6.94–6.91 (m, 4.0 H), 5.25 (dd, J = 11.3, 2.7 Hz, 0.67 H), 5.11 (dd, J = 9.3, 4.7 Hz, 0.33 H), 4.30–3.97 (m, 4.0 H), 3.88 (s, 1.0 H), 3.87 (s, 2.0 H), 3.84 (s, 3.0 H), 2.33–2.22 (m, 1.0 H), 1.95–1.86 (m, 1.0 H), 1.84–1.78 (m, 0.33 H), 1.63–1.57 (m, 0.67 H), 1.35 (t, J = 7.3 Hz, 2.0 H), 1.34–1.24 (m, 2.0 H), 1.23–1.18 (m, 2.0 H), 1.10 (t, J = 7.3 Hz, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 190.5, 190.1, 169.4, 169.4, 167.4, 167.4, 164.3, 164.1, 164.1, 131.8, 131.7, 131.5, 130.2, 129.8, 127.7, 114.0, 114.0, 113.9, 69.0, 68.2, 63.1, 62.0, 61.9, 61.6, 61.5, 56.4, 55.6, 55.6, 55.6, 34.4, 33.9, 28.1, 27.7, 24.7, 24.5, 20.5, 20.1, 14.1, 14.0, 13.9, 13.9; IR: ῡ = 1720, 1679, 1583, 1318, 1135, 804 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO9S+, 541.1503, found 541.1496.
Diethyl 2-(3-(3-methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)-3-oxopropyl)cyclopropane-1,1-dicarboxylate (3l): Colorless oil (45.7 mg, 44% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.63 (t, J = 8.0 Hz, 2.0 H), 7.54 (d, J = 8.0 Hz, 1.0 H), 7.44 (s, 1.0 H), 7.39–7.34 (m, 1.0 H), 7.15–7.12 (m, 1.0 H), 6.94–6.91 (m, 2.0 H), 5.31 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.15 (dd, J = 9.3, 4.7 Hz, 0.33 H), 4.31–3.98 (m, 4.0 H), 3.85 (s, 6.0 H), 2.37–2.23 (m, 1.0 H), 1.97–1.92 (m, 1.0 H), 1.85–1.78 (m, 0.33 H), 1.63–1.57 (m, 0.67 H), 1.36 (t, J = 7.3 Hz, 3.0 H), 1.32–1.24 (m, 2.0 H), 1.23–1.18 (m, 2.0 H), 1.11 (t, J = 7.3 Hz, 3.0 H); 13C NMR (126 MHz, CDCl3): δc 192.6, 192.1, 169.4, 169.4, 167.4, 167.4, 164.2, 164.2, 159.8, 159.8, 138.5, 138.1, 131.9, 129.7, 129.7, 127.7, 127.6, 121.9, 121.7, 120.8, 120.7, 114.1, 114.1, 113.0, 112.7, 69.5, 68.6, 62.0, 61.6, 61.6, 61.5, 55.7, 55.6, 55.5, 55.4, 34.4, 33.9, 28.3, 27.8, 24.7, 24.4, 20.5, 20.1, 14.1, 14.0, 13.9, 13.8; IR: ῡ = 1720, 1679, 1583, 1318, 1135, 804 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO9S+, 541.1503, found 541.1495.
Diethyl 2-(3-(2-methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)-3-oxopropyl)cyclopropane-1,1-dicarboxylate (3m): Colorless oil (44.5 mg, 43% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.60–7.55 (m, 3.0 H), 7.47–7.42 (m, 1.0 H), 6.97 (t, J = 7.5 Hz, 1.0 H), 6.89–6.85 (m, 3.0 H), 5.82 (dd, J = 11.5, 3.0 Hz, 0.67 H), 5.67 (dd, J = 9.7, 3.7 Hz, 0.33 H), 4.34–4.07 (m, 4.0 H), 3.89 (s, 1.0 H), 3.88 (s, 2.0 H), 3.83 (s, 3.0 H), 2.47–2.41 (m, 0.33 H), 2.34–2.28 (m, 1.0 H), 1.98–1.87 (m, 1.0 H), 1.84–1.78 (m, 1.0 H), 1.42–1.37 (m, 1.67 H), 1.34 (t, J = 7.3 Hz, 3.0 H), 1.19 (t, J = 7.3 Hz, 3.0 H); 13C NMR (126 MHz, CDCl3): δc 194.0, 193.6, 169.9, 169.7, 167.5, 167.4, 163.9, 163.8, 158.5, 158.4, 134.7, 134.6, 131.5, 131.5, 131.3, 131.2, 128.5, 128.4, 127.9, 127.7, 120.9, 120.8, 113.8, 111.6, 111.6, 73.0, 72.5, 61.8, 61.5, 61.5, 61.4, 55.6, 55.4, 34.5, 34.2, 27.2, 27.0, 25.1, 25.0, 20.9, 20.5, 14.1, 14.1, 14.0, 14.0; IR: ῡ = 1720, 1679, 1583, 1318, 1135, 804 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO9S+, 541.1503, found 541.1501.
Diethyl 2-((2-benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (4a): Colorless oil (63.4 mg, 67% yield, dr = 2.0:1; 4.5 mmol scale, 1.413 g, 64% yield). 1H NMR (500 MHz, CDCl3): δH 8.14 (d, J = 7.5 Hz, 1.34 H), 8.07 (d, J = 7.5 Hz, 0.66 H), 7.81 (d, J = 8.5 Hz, 0.33 H), 7.76 (d, J = 8.5 Hz, 0.67 H), 7.65–7.59 (m, 1.0 H), 7.54–7.48 (m, 2.0 H), 7.33 (s, 0.33 H), 7.26–7.23 (m, 1.0 H), 7.18 (s, 0.67 H), 5.41 (dd, J = 10.5, 3.5 Hz, 0.67 H), 5.19 (dd, J = 11.0, 4.5 Hz, 0.33 H), 4.30–4.10 (m, 4.0 H), 3.61 (dd, J = 11.0, 5.0 Hz, 0.33 H), 3.46 (t, J = 7.3 Hz, 0.67 H), 3.25–3.20 (m, 1.0 H), 3.07–3.00 (m, 0.67 H), 2.79–2.70 (m, 0.67 H), 2.59–2.44 (m, 1.33 H), 2.41 (s, 3.0 H), 2.39–2.23 (m, 1.67 H), 1.31–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.9, 189.8, 169.0, 168.9, 168.6, 144.1, 143.6, 139.7, 139.7, 136.4, 136.3, 135.1, 135.0, 134.3, 134.3, 129.7, 129.6, 129.5, 129.0, 128.7, 128.7, 128.4, 128.3, 124.6, 124.2, 63.6, 61.9, 61.8, 61.4, 49.9, 49.2, 34.7, 34.5, 34.5, 33.7, 30.3, 28.7, 21.7, 21.5, 14.1, 14.0, 14.0, 14.0; IR: ῡ = 1726, 1682, 1596, 1447, 1137, 735 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H26NaO7S+, 495.1448, found 495.1436.
Diethyl 2-((2-benzoyl-6-(tert-butyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4b): Colorless oil (59.6 mg, 61% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.16 (d, J = 7.3 Hz, 1.34 H), 8.08 (d, J = 7.3 Hz, 0.66 H), 7.86 (d, J = 7.5 Hz, 0.33 H), 7.80 (d, J = 7.5 Hz, 0.67 H), 7.65–7.60 (m, 1.0 H), 7.52 (t, J = 7.7 Hz, 2.0 H), 7.49–7.46 (m, 1.33 H), 7.34 (d, J = 2.5 Hz, 0.67 H), 5.44 (dd, J = 11.3, 4.0 Hz, 0.67 H), 5.19 (dd, J = 11.3, 4.0 Hz, 0.33 H), 4.29–4.12 (m, 4.0 H), 3.59 (dd, J = 9.3, 5.3 Hz, 0.33 H), 3.44 (t, J = 7.3 Hz, 0.67 H), 3.27–3.21 (m, 1.0 H), 3.10–3.04 (m, 0.67 H), 2.83–2.68 (m, 0.67 H), 2.60–2.54 (m, 0.33 H), 2.47–2.42 (m, 0.67 H), 2.40–2.33 (m, 1.67 H), 1.34 (s, 9.0 H), 1.29–1.24 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.8, 189.7, 169.0, 169.0, 168.9, 168.6, 157.0, 156.6, 139.3, 139.1, 136.4, 135.3, 135.2, 134.3, 134.2, 129.7, 129.5, 128.7, 128.7, 126.1, 125.6, 124.9, 124.8, 124.4, 124.0, 63.8, 61.9, 61.8, 61.8, 61.6, 50.0, 49.2, 35.3, 35.1, 34.9, 34.8, 34.3, 31.0, 30.9, 30.5, 29.1, 14.0, 14.0, 14.0; IR: ῡ = 1725, 1596, 1448, 1304, 1143, 732 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C28H34NaO7S+, 537.1917, found 537.1929.
Diethyl 2-((2-benzoyl-6-methoxy-1,1-dioxidothiochroman-4-yl)methyl)malonate (4c): Colorless oil (59.6 mg, 61% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.14 (d, J = 7.7 Hz, 1.34 H), 8.06 (d, J = 7.7 Hz, 0.66 H), 7.84 (d, J = 9.0 Hz, 0.33 H), 7.80 (d, J = 9.0 Hz, 0.67 H), 7.65–7.60 (m, 1.0 H), 7.53–7.48 (m, 2.0 H), 7.00 (d, J = 2.5 Hz, 0.33 H), 6.93 (dt, J = 7.7, 2.3 Hz, 1.0 H), 6.86 (d, J = 2.5 Hz, 0.67 H), 5.40 (dd, J = 10.3, 4.5 Hz, 0.67 H), 5.21 (dd, J = 10.3, 4.5 Hz, 0.33 H), 4.27–4.13 (m, 4.0 H), 3.88 (s, 1.0 H), 3.86 (s, 2.0 H), 3.60 (dd, J = 9.5, 5.5 Hz, 0.33 H), 3.47 (t, J = 7.3 Hz, 0.67 H), 3.28–3.21 (m, 1.0 H), 3.07–3.01 (m, 0.67 H), 2.74–2.67 (m, 0.67 H), 2.58–2.45 (m, 1.0 H), 2.38–2.28 (m, 1.67 H), 1.29–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 190.1, 189.9, 169.0, 168.9, 168.9, 168.6, 163.3, 162.7, 142.3, 142.1, 136.4, 136.4, 134.3, 134.2, 129.7, 129.6, 129.5, 128.7, 127.0, 126.4, 114.1, 113.9, 112.9, 112.9, 63.8, 61.9, 61.8, 61.6, 55.6, 55.6, 49.9, 49.2, 34.7, 34.4, 34.1, 33.9, 30.7, 29.2, 14.0, 14.0, 14.0; IR: ῡ = 1684, 1595, 1448, 1294, 1134, 742 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H28NaO8S+, 511.1397, found 511.1389.
Diethyl 2-((2-benzoyl-6-bromo-1,1-dioxidothiochroman-4-yl)methyl)malonate (4d): Colorless oil (35.4 mg, 33% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.12 (d, J = 8.5 Hz, 1.34 H), 8.05 (d, J = 8.5 Hz, 0.66 H), 7.78 (d, J = 8.5 Hz, 0.33 H), 7.74 (d, J = 8.5 Hz, 0.67 H), 7.71 (s, 0.33 H), 7.67–7.62 (m, 1.0 H), 7.60–7.56 (m, 1.67 H), 7.54–7.49 (m, 2.0 H), 5.41 (dd, J = 10.7, 4.0 Hz, 0.67 H), 5.21 (dd, J = 10.7, 4.0 Hz, 0.33 H), 4.29–4.13 (m, 4.0 H), 3.59 (dd, J = 9.7, 5.3 Hz, 0.33 H), 3.45 (t, J = 7.3 Hz, 0.67 H), 3.29–3.23 (m, 1.0 H), 3.59 (dd, J = 9.7, 5.3 Hz, 0.33 H), 3.45 (t, J = 7.3 Hz, 0.67 H), 3.29–3.23 (m, 1.0 H), 3.05–2.99 (m, 0.67 H), 2.75–2.68 (m, 0.67 H), 2.61–2.56 (m, 0.33 H), 2.50–2.44 (m, 0.67 H), 2.41–2.24 (m, 1.67 H), 1.31–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.5, 189.5, 168.8, 168.7, 168.5, 141.9, 141.8, 136.7, 136.1, 136.1, 134.5, 134.5, 132.2, 131.5, 131.0, 130.9, 129.6, 129.5, 128.8, 128.4, 127.7, 126.3, 125.9, 63.5, 62.0, 62.0, 61.3, 49.7, 49.0, 34.4, 34.3, 33.7, 30.3, 28.7, 14.1, 14.0, 14.0,14.0; IR: ῡ = 1723, 1682, 1581, 1447, 1148, 742 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H25BrNaO7S+, 559.0397, found 559.0378.
Diethyl 2-((2-benzoyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (4e): Colorless oil (36.7 mg, 40% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.15 (d, J = 7.5 Hz, 1.34 H), 8.07 (d, J = 7.5 Hz, 0.66 H), 7.93 (d, J = 8.0 Hz, 0.33 H), 7.88 (d, J = 8.0 Hz, 0.67 H), 7.66–7.59 (m, 1.33 H), 7.57–7.48 (m, 3.0 H), 7.47–7.43 (m, 1.0 H), 7.40 (d, J = 8.0 Hz, 0.67 H), 5.44 (dd, J = 11.0, 4.0 Hz, 0.67 H), 5.21 (dd, J = 11.0, 4.0 Hz, 0.33 H), 4.28–4.12 (m, 4.0 H), 3.60 (dd, J = 9.7, 5.3 Hz, 0.33 H), 3.47 (t, J = 7.3 Hz, 0.67 H), 3.30–3.25 (m, 1.0 H), 3.09–3.03 (m, 0.67 H), 2.80–2.72 (m, 0.67 H), 2.61–2.56 (m, 0.33 H), 2.49–2.26 (m, 2.33 H), 1.30–1.22 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.7, 189.7, 168.9, 168.9, 168.9, 168.6, 139.8, 139.7, 138.0, 138.0, 136.3, 134.4, 134.3, 133.3, 132.9, 129.7, 129.5, 129.5, 129.4, 128.8, 128.2, 128.0, 127.6, 124.6, 124.2, 63.6, 61.9, 61.8, 61.4, 49.9, 49.2, 34.7, 34.6, 34.4, 33.9, 30.3, 28.7, 14.0, 14.0, 14.0; IR: ῡ = 1724, 1683, 1595, 1448, 1294, 741 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H26NaO7S+, 481.1291, found 481.1277.
Diethyl 2-((2-benzoyl-8-methyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (4f): Colorless oil (32.2 mg, 34% yield, dr = 4.0:1). 1H NMR (500 MHz, CDCl3): δH 8.21 (d, J = 8.0 Hz, 1.6 H), 8.12 (d, J = 8.0 Hz, 0.4 H), 7.67–7.62 (m, 1.0 H), 7.57–7.50 (m, 2.2 H), 7.37 (t, J = 8.0 Hz, 1.0 H), 7.21–7.17 (m, 1.8 H), 5.53 (dd, J = 12.7, 2.7 Hz, 0.8 H), 5.17 (dd, J = 12.7, 2.7 Hz, 0.2 H), 4.28–4.11 (m, 4.0 H), 3.58–3.55 (m, 0.2 H), 3.43 (t, J = 7.5 Hz, 0.8 H), 3.21–3.16 (m, 1.0 H), 3.10–3.03 (m, 1.0 H), 2.70 (s, 0.6 H), 2.68 (s, 2.4 H), 2.41 (t, J = 7.5 Hz, 1.6 H), 2.30–2.26 (m, 1.0 H), 2.24–2.18 (m, 0.4 H), 1.31–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.4, 169.0, 169.0, 168.6, 139.6, 137.5, 137.0, 136.5, 134.4, 132.1, 132.0, 131.9, 129.9, 129.8, 129.7, 128.7, 128.7, 127.6, 65.0, 62.8, 62.0, 61.9, 61.9, 61.8, 50.1, 49.9, 35.8, 35.4, 34.5, 34.1, 27.5, 20.2, 14.1, 14.0, 14.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H28NaO7S+, 495.1448, found 495.1427.
Diethyl 2-((2-benzoyl-8-methyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (4g): Colorless oil (40.7 mg, 43% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.20 (d, J = 7.7 Hz, 1.34 H), 8.15 (d, J = 7.7 Hz, 0.66 H), 7.75 (d, J = 7.7 Hz, 0.66 H), 7.68–7.62 (m, 1.34 H), 7.56–7.49 (m, 2.0 H), 7.42–7.39 (m, 0.67 H), 7.34 (d, J = 7.7 Hz, 1.0 H), 7.28 (d, J = 7.7 Hz, 0.33 H), 5.55 (dd, J = 12.3, 3.3 Hz, 0.67 H), 5.42 (dd, J = 10.7, 3.3 Hz, 0.33 H), 4.26–4.09 (m, 4.0 H), 3.47–3.44 (m, 1.0 H), 3.37–3.34 (m, 0.67 H), 3.24–3.20 (m, 0.33 H), 3.08–2.97 (m, 1.0 H), 2.78–2.71 (m, 0.33 H), 2.44 (s, 2.0 H), 2.41–2.31 (m, 3.67 H), 1.30–1.20 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.8, 189.5, 169.0, 168.9, 168.7, 168.5, 138.8, 138.3, 136.5, 136.5, 135.0, 134.4, 133.8, 129.7, 129.7, 129.6, 129.3, 128.8, 128.7, 128.0, 124.2, 122.2, 62.0, 61.9, 61.9, 61.8, 61.3, 61.2, 50.0, 49.9, 34.5, 34.2, 33.7, 32.1, 31.0, 28.9, 26.9, 21.0, 19.1, 14.0, 14.0, 14.0, 13.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H28NaO7S+, 495.1448, found 495.1420.
Diethyl 2-((6-methyl-2-(4-methylbenzoyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4h): Colorless oil (66.2 mg, 68% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.04 (d, J = 8.3 Hz, 1.34 H), 7.97 (d, J = 8.3 Hz, 0.66 H), 7.81(d, J = 8.3 Hz, 0.33 H), 7.76 (d, J = 8.3 Hz, 0.67 H), 7.32–7.28 (m, 2.33 H), 7.25–7.22 (m, 1.0 H), 7.18 (s, 0.67 H), 5.38 (dd, J = 10.7, 4.0 Hz, 0.67 H), 5.16 (dd, J = 10.7, 4.0 Hz, 0.33 H), 4.29–4.12 (m, 4.0 H), 3.61 (dd, J = 10.0, 5.0 Hz, 0.33 H), 3.46 (t, J = 7.5 Hz, 0.67 H), 3.24–3.20 (m, 1.0 H), 3.06–3.00 (m, 0.67 H), 2.79–2.69 (m, 0.67 H), 2.58–2.53 (m, 0.33 H), 2.49–2.44 (m, 0.67 H), 2.43 (s, 3.0 H), 2.42 (s, 1.0 H), 2.41 (s, 2.0 H), 2.38–2.30 (m, 1.67 H), 1.31–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.2, 169.0, 168.9, 168.7, 145.5, 145.5, 144.0, 143.6, 139.7, 135.2, 135.1, 133.9, 133.9, 129.8, 129.7, 129.7, 129.4, 129.4, 128.9, 128.4, 128.3, 124.6, 124.2, 63.4, 61.9, 61.8, 61.2, 49.9, 49.1, 34.7, 34.5, 34.5, 33.8, 30.2, 28.7, 21.8, 21.7, 21.6, 14.1, 14.0, 14.0, 14.0; IR: ῡ = 1725, 1678, 1603, 1447, 1136, 729 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO7S+, 509.1604, found 509.1606.
Diethyl 2-((2-(4-methoxybenzoyl)-6-methyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (4i): Colorless oil (62.5 mg, 62% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.13 (d, J = 9.0 Hz, 1.34 H), 8.05 (d, J = 8.7 Hz, 0.66 H), 7.80 (d, J = 8.0 Hz, 0.33 H), 7.75 (d, J = 8.0 Hz, 0.67 H), 7.32 (s, 0.33 H), 7.23 (d, J = 8.0 Hz, 1.0 H), 7.17 (s, 0.67 H), 6.99–6.94 (m, 2.0 H), 5.34 (dd, J = 10.7, 3.3 Hz, 0.67 H), 5.12 (dd, J = 11.3, 4.3 Hz, 0.33 H), 4.26–4.11 (m, 4.0 H), 3.88 (s, 2.0 H), 3.86 (s, 1.0 H), 3.61 (dd, J = 10.0, 5.0 Hz, 0.33 H), 3.46 (t, J = 7.3 Hz, 0.67 H), 3.23–3.17 (m, 1.0 H), 3.05–2.99 (m, 0.67 H), 2.78–2.69 (m, 0.67 H), 2.58–2.53 (m, 0.33 H), 2.48–2.44 (m, 0.67 H), 2.43 (s, 1.0 H), 2.41 (s, 2.0 H), 2.37–2.22 (m, 1.67 H), 1.29–1.22 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 187.8, 187.7, 169.0, 168.9, 168.7, 168.7, 164.5, 164.5, 143.9, 143.5, 139.7, 139.7, 135.3, 135.1, 132.2, 132.1, 129.7, 129.5, 129.4, 128.9, 128.4, 128.2, 124.6, 124.2, 113.9, 113.9, 63.3, 61.8, 61.8, 61.0, 55.5, 49.9, 49.1, 34.5, 33.8, 30.2, 28.6, 21.7, 21.5, 14.0, 14.0, 14.0, 14.0; IR: ῡ = 1743, 1721, 1598, 1134, 1023, 687 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO8S+, 525.1554, found 525.1534.
Diethyl 2-((2-(4-bromobenzoyl)-6-methyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (4j): Colorless oil (36.4 mg, 33% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.01 (d, J = 8.7 Hz, 1.34 H), 7.94 (d, J = 8.5 Hz, 0.66 H), 7.80 (d, J = 8.0 Hz, 0.33 H), 7.75 (d, J = 8.0 Hz, 0.67 H), 7.66 (d, J = 8.7 Hz, 1.34 H), 7.64 (d, J = 8.7 Hz, 0.66 H), 7.33 (s, 0.33 H), 7.24 (d, J = 8.0 Hz, 1.0 H), 7.17 (s, 0.67 H), 5.36 (dd, J = 10.7, 3.3 Hz, 0.67 H), 5.12 (dd, J = 11.0, 4.5 Hz, 0.33 H), 4.28–4.12 (m, 4.0 H), 3.60 (dd, J = 10.0, 5.0 Hz, 0.33 H), 3.46 (t, J = 7.3 Hz, 0.67 H), 3.25–3.19 (m, 1.0 H), 3.05–2.99 (m, 0.67 H), 2.79–2.69 (m, 0.67 H), 2.58–2.53 (m, 0.33 H), 2.47–2.41 (m, 3.67 H), 2.36–2.23 (m, 1.67 H), 1.30–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.0, 188.9, 169.0, 168.9, 168.6, 144.2, 143.8, 139.7, 139.6, 135.1, 135.0, 134.9, 132.1, 131.1, 131.0, 130.0, 129.9, 129.8, 129.1, 128.4, 128.4, 124.7, 124.2, 63.8, 61.9, 61.8, 61.5, 50.0, 49.2, 34.7, 34.4, 33.7, 30.1, 28.5, 21.8, 21.6, 14.1, 14.0, 14.0, 14.0; IR: ῡ = 1724, 1683, 1583, 1447, 1137, 732 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27BrNaO7S+, 573.0553, found 573.0548.
Diethyl 2-((6-fluoro-2-(4-methylbenzoyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4k): Colorless oil (57.1 mg, 58% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.01 (d, J = 8.3 Hz, 1.34 H), 7.95 (d, J = 8.3 Hz, 0.66 H), 7.93–7.87 (m, 1.0 H), 7.32–7.28 (m, 2.0 H), 7.27–7.24 (m, 0.33 H), 7.15–7.11 (m, 1.67 H), 5.37 (dd, J = 10.0, 4.0 Hz, 0.67 H), 5.20 (dd, J = 10.0, 4.0 Hz, 0.33 H), 4.29–4.13 (m, 4.0 H), 3.59 (dd, J = 9.5, 5.0 Hz, 0.33 H), 3.46 (t, J = 7.3 Hz, 0.67 H), 3.31–3.23 (m, 1.0 H), 3.05–2.99 (m, 0.67 H), 2.74–2.67 (m, 0.67 H), 2.61–2.56 (m, 0.33 H), 2.49–2.24 (m, 5.33 H), 1.31–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.0, 189.0, 168.8, 168.7, 168.7, 168.5, 165.3 (d, J = 255.8 Hz), 164.7 (d, J = 255.8 Hz), 145.7, 145.7, 143.5 (d, J = 8.2 Hz), 143.4 (d, J = 8.2 Hz), 133.8 (d, J = 3.3 Hz), 133.8, 133.7, 129.8, 129.7, 129.5, 127.7 (d, J = 9.5 Hz), 127.2 (d, J = 9.5 Hz), 116.1 (d, J = 22.7 Hz), 115.8 (d, J = 22.7 Hz), 115.1 (d, J = 23.5 Hz), 114.9 (d, J = 23.5 Hz), 63.4, 62.0, 61.9, 61.2, 49.7, 49.1, 34.5, 34.5, 34.1, 33.9, 30.4, 28.9, 21.8, 21.7, 14.0, 14.0, 14.0, 14.0; IR: ῡ = 1725, 1678, 1605, 1305, 1148, 732 cm1; 19F NMR (470 MHz, CDCl3): δF −103.4, −104.2 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27FNaO7S+, 513.1354, found 513.1349.
Diethyl 2-((6-fluoro-2-(4-methoxybenzoyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4l): Colorless oil (56.8 mg, 56% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.09 (d, J = 8.7 Hz, 1.34 H), 8.02 (d, J = 8.7 Hz, 0.66 H), 7.93–7.86 (m, 1.0 H), 7.26–7.23 (m, 0.33 H), 7.14–7.10 (m, 1.67 H), 6.97–6.93 (m, 2.0 H), 5.33 (dd, J = 10.3, 4.3 Hz, 0.66 H), 5.16 (dd, J = 10.3, 4.3 Hz, 0.34 H), 4.26–4.12 (m, 4.0 H), 3.87 (s, 2.0 H), 3.86 (s, 1.0 H), 3.58 (dd, J = 9.7, 5.3 Hz, 0.33 H), 3.47–3.44 (m, 0.67 H), 3.30–3.21 (m, 1.0 H), 3.04–2.98 (m, 0.67 H), 2.73–2.66 (m, 0.67 H), 2.59–2.54 (m, 0.33 H), 2.48–2.22 (m, 2.33 H), 1.29–1.22 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 187.6, 187.5, 168.8, 168.7, 168.7, 168.5, 164.7, 164.6, 165.2 (d, J = 255.7 Hz), 164.7 (d, J = 255.4 Hz), 143.5 (d, J = 8.3 Hz), 143.4 (d, J = 9.5 Hz), 134.0 (d, J = 3.0 Hz), 133.9 (d, J = 2.9 Hz), 132.1, 132.0, 129.3, 129.2, 127.6 (d, J = 9.5 Hz), 127.2 (d, J = 9.5 Hz), 116.0 (d, J = 22.8 Hz), 115.7 (d, J = 22.9 Hz), 115.2, 114.8 (d, J = 22.9 Hz), 114.0, 114.0, 63.2, 61.9, 61.9, 60.9, 55.5, 49.7, 49.1, 34.6, 34.5, 34.2, 33.9, 30.3, 28.8, 14.0, 14.0, 13.9, 13.9; IR: ῡ = 1724, 1672, 1597, 1172, 1026, 731 cm1; 19F NMR (470 MHz, CDCl3): δF −103.5, −104.3 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27FNaO8S+, 529.1303, found 529.1295.
Diethyl 2-((6-bromo-2-(4-methoxybenzoyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4m): Colorless oil (62.3 mg, 55% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.08 (d, J = 8.7 Hz, 1.34 H), 8.01 (d, J = 8.7 Hz, 0.66 H), 7.75 (d, J = 8.7 Hz, 0.33 H), 7.71 (d, J = 8.7 Hz, 0.67 H), 7.68 (s, 0.33 H), 7.57–7.54 (m, 1.67 H), 6.97–6.93 (m, 2.0 H), 5.34 (dd, J = 10.0, 3.5 Hz, 0.67 H), 5.14 (dd, J = 10.7, 4.7 Hz, 0.33 H), 4.28–4.12 (m, 4.0 H), 3.87 (s, 2.0 H), 3.86 (s, 1.0 H), 3.58 (dd, J = 9.7, 4.7 Hz, 0.33 H), 3.45 (t, J = 7.5 Hz, 0.67 H), 3.27–3.20 (m, 1.0 H), 3.02–2.96 (m, 0.67 H), 2.73–2.66 (m, 0.67 H), 2.58–2.53 (m, 0.33 H), 2.47–2.41 (m, 0.67 H), 2.38–2.22 (m, 1.67 H), 1.28–1.22 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 187.4, 168.8, 168.7, 168.7, 168.4, 164.6, 164.6, 141.9, 141.9, 136.9, 136.8, 132.2, 132.1, 132.0, 131.3, 130.9, 130.8, 129.2, 129.1, 128.2, 127.5, 126.2, 125.8, 114.0, 114.0, 63.1, 61.9, 61.9, 60.8, 55.5, 49.7, 49.0, 34.4, 34.3, 34.3, 33.8, 30.1, 28.6, 14.0, 14.0, 13.9, 13.9; IR: ῡ = 1737, 1674, 1599, 1258, 1138, 840 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27BrNaO8S+, 589.0502, found 589.0521.
Diethyl 2-((2-(4-fluorobenzoyl)-6-methoxy-1,1-dioxidothiochroman-4-yl)methyl)malonate (4n): Colorless oil (58.9 mg, 58% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.18 (dd, J = 8.7, 5.3 Hz, 1.34 H), 8.10 (dd, J = 8.7, 5.3 Hz, 0.66 H), 7.82 (d, J = 8.7 Hz, 0.33 H), 7.78 (d, J = 8.7 Hz, 0.67 H), 7.20–7.14 (m, 2.0 H), 7.00 (d, J = 1.7 Hz, 0.33H), 6.94–6.91 (m, 1.0 H), 6.85 (d, J = 1.7 Hz, 0.67 H), 5.35 (dd, J = 10.5, 4.3 Hz, 0.67 H), 5.15 (dd, J = 10.5, 4.3 Hz, 0.33 H), 4.27–4.12 (m, 4.0 H), 3.88 (s, 1.0 H), 3.86 (s, 2.0 H), 3.59 (dd, J = 9.5, 5.5 Hz, 0.33 H), 3.47 (t, J = 7.3 Hz, 0.67 H), 3.24–3.22 (m, 1.0 H), 3.05–2.99 (m, 0.67 H), 2.73–2.66 (m, 0.67 H), 2.57–2.52 (m, 0.33 H), 2.48–2.42 (m, 0.67 H), 2.37–2.27 (m, 1.67 H), 1.30–1.22 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 188.4, 188.3, 169.0, 168.9, 168.9, 168.6, 166.5 (d, J = 258.0 Hz), 163.4 (d, J = 258.0 Hz), 163.3, 162.8, 142.2, 142.1, 132.9 (d, J = 2.9 Hz), 132.8 (d, J = 2.9 Hz), 132.5 (d, J = 9.6 Hz), 132.4 (d, J = 9.6 Hz), 129.6, 129.5, 127.0, 126.4, 115.9 (d, J = 22.1 Hz), 114.0 (d, J = 30.9 Hz), 112.9 (d, J = 5.3 Hz), 63.8, 61.9, 61.9, 61.8, 61.6, 55.6, 55.6, 49.9, 49.2, 34.8, 34.3, 34.2, 33.9, 30.5, 29.0, 14.0, 14.0, 14.0; IR: ῡ = 1682,1595, 1448, 1294, 1134, 730 cm1; 19F NMR (470 MHz, CDCl3): δF −102.8 (s) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27FNaO8S+, 529.1303, found 529.1306.
Diethyl 2-((2-(4-bromobenzoyl)-6-methoxy-1,1-dioxidothiochroman-4-yl)methyl)malonate (4o): Colorless oil (33.0 mg, 29% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.01 (d, J = 8.7 Hz, 1.34 H), 7.93 (d, J = 8.7 Hz, 0.66 H), 7.83 (d, J = 8.7 Hz, 0.33 H), 7.79 (d, J = 8.7 Hz, 0.67 H), 7.67–7.63 (m, 2.0 H), 7.01 (s, 0.33 H), 6.93 (dd, J = 8.7, 2.3 Hz, 1.0 H), 6.85 (d, J = 2.3 Hz, 0.67 H), 5.34 (dd, J = 10.0, 3.5 Hz, 0.67 H), 5.14 (dd, J = 10.5, 5.0 Hz, 0.33 H), 4.28–4.11 (m, 4.0 H), 3.89 (s, 1.0 H), 3.87 (s, 2.0 H), 3.60 (dd, J = 9.0, 5.5 Hz, 0.33 H), 3.47 (t, J = 7.3 Hz, 0.67 H), 3.25–3.23 (m, 1.0 H), 3.06–3.00 (m, 0.67 H), 2.74–2.66 (m, 0.67 H), 2.57–2.52 (m, 0.33 H), 2.49–2.43 (m, 0.67 H), 2.37–2.28 (m, 1.67 H), 1.31–1.22 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.1, 189.1, 169.0, 168.9, 168.6, 163.4, 162.8, 142.3, 142.1, 135.1, 135.1, 132.1, 131.1, 131.0, 129.9, 129.6, 129.4, 127.1, 126.5, 114.2, 113.9, 113.0, 112.9, 64.0, 61.9, 61.9, 61.7, 55.7, 55.6, 50.0, 49.2, 34.9, 34.4, 34.1, 33.9, 30.5, 29.0, 14.1, 14.0, 14.0; IR: ῡ = 1732, 1664, 1592, 1248, 1131, 848 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27BrNaO8S+, 589.0502, found 589.0515.
Diethyl 2-((6-fluoro-2-(3-methoxybenzoyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4p): Colorless oil (29.6 mg, 29% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.95–7.88 (m, 1.0 H), 7.73 (d, J = 8.0 Hz, 0.67 H), 7.64 (d, J = 8.0 Hz, 0.33 H), 7.60 (s, 0.67 H), 7.55 (s, 0.33 H), 7.45–7.40 (m, 1.0 H), 7.27–7.25 (m, 0.67 H), 7.19 (dd, J = 8.5, 2.5 Hz, 0.67 H), 7.17–7.12 (m, 1.67 H), 5.37 (dd, J = 9.7, 3.7 Hz, 0.67 H), 5.21 (dd, J = 10.5, 5.0 Hz, 0.33 H), 4.29–4.13 (m, 4.0 H), 3.86 (s, 2.0 H), 3.85 (s, 1.0 H), 3.59 (dd, J = 9.7, 5.3 Hz, 0.33 H), 3.46 (t, J = 7.3 Hz, 0.67 H), 3.31–3.25 (m, 1.0 H), 3.06–3.00 (m, 0.67 H), 2.74–2.66 (m, 0.67 H), 2.62–2.57 (m, 0.33 H), 2.50–2.24 (m, 2.33 H), 1.31–1.23 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 189.6, 189.5, 168.8, 168.7, 168.7, 168.5, 165.4 (d, J = 255.9 Hz), 164.8 (d, J = 255.9 Hz), 159.9, 143.5 (d, J = 8.2 Hz), 143.3 (d, J = 8.2 Hz), 137.5, 137.4, 133.8 (d, J = 3.2 Hz), 133.8 (d, J = 3.2 Hz), 129.8, 129.8, 127.8 (d, J = 9.6 Hz), 127.3 (d, J = 9.6 Hz), 122.5, 122.4, 121.4, 121.2, 116.1 (d, J = 22.7 Hz), 115.8 (d, J = 22.7 Hz), 115.1 (d, J = 23.1 Hz), 114.9 (d, J = 23.1 Hz), 113.2, 113.2, 63.7, 62.0, 61.9, 61.6, 55.5, 49.7, 49.1, 34.5, 34.4, 34.0, 33.8, 30.6, 29.1, 14.0, 14.0, 14.0, 14.0; 19F NMR (470 MHz, CDCl3): δF −103.2, −104.1 (s) ppm; IR: ῡ = 1724, 1682, 1580, 1146, 1026, 730 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27FNaO8S+, 529.1303, found 529.1291.
Diethyl 2-((6-fluoro-2-(2-methoxybenzoyl)-1,1-dioxidothiochroman-4-yl)methyl)malonate (4q): Colorless oil (54.8 mg, 54% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 7.90–7.83 (m, 1.0 H), 7.68 (dd, J = 7.7, 1.7 Hz, 0.33 H), 7.60 (dd, J = 7.7, 1.7 Hz, 0.67 H), 7.52 (td, J = 7.7, 1.7 Hz, 1.0 H), 7.23 (dd, J = 10.0, 1.5 Hz, 0.33 H), 7.14–7.08 (m, 1.67 H), 7.04–6.99 (m, 2.0 H), 5.77 (dd, J = 9.0, 3.5 Hz, 0.67 H), 5.60 (dd, J = 10.0, 6.0 Hz, 0.33 H), 4.29–4.17 (m, 4.0 H), 3.96 (s, 2.0 H), 3.93 (s, 1.0 H), 3.59 (dd, J = 9.3, 5.7 Hz, 0.33 H), 3.49 (dd, J = 9.0, 6.0 Hz, 0.67 H), 3.31–3.20 (m, 1.0 H), 2.96–2.90 (m, 0.67 H), 2.72–2.66 (m, 0.67 H), 2.54–2.47 (m, 1.67 H), 2.33–2.22 (m, 1.0 H), 1.32–1.25 (m, 6.0 H); 13C NMR (126 MHz, CDCl3): δc 192.1, 192.1, 168.8, 168.8, 168.6, 165.3 (d, J = 255.5 Hz), 164.7 (d, J = 255.5 Hz), 158.8, 158.7, 143.9 (d, J = 8.4 Hz), 143.3 (d, J = 8.4 Hz), 135.1, 134.9, 134.2 (d, J = 3.2 Hz), 133.7 (d, J = 3.2 Hz), 131.1, 130.9, 127.7 (d, J = 9.6 Hz), 127.5, 127.2, 126.9 (d, J = 9.6 Hz), 121.2, 116.1 (d, J = 22.7 Hz), 115.5 (d, J = 22.7 Hz), 114.8 (d, J = 22.8 Hz), 114.3 (d, J = 22.8 Hz), 111.7, 111.7, 68.0, 65.1, 61.9, 61.9, 55.9, 55.8, 49.5, 49.2, 34.9, 34.0, 33.4, 33.3, 30.8, 28.5, 14.0, 14.0, 14.0, 14.0; 19F NMR (470 MHz, CDCl3): δF −103.7, −104.7 (s) ppm; IR: ῡ = 1726, 1597, 1299, 1147, 1020, 730 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C25H27FNaO8S+, 529.1303, found 529.1319.
Diethyl 2-((2-benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)methyl)-2-methylmalonate (5ab): Colorless oil (43.7 mg, 45% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.18 (dd, J = 8.3, 1.3 Hz, 1.34 H), 8.06 (dd, J = 8.3, 1.3 Hz, 0.66 H), 7.79 (d, J = 8.3 Hz, 0.33 H), 7.75 (d, J = 8.3 Hz, 0.67 H), 7.65–7.60 (m, 1.0 H), 7.55–7.48 (m, 2.0 H), 7.33 (s, 0.33 H), 7.23 (d, J = 8.3 Hz, 1.0 H), 7.12 (s, 0.67 H), 5.59 (dd, J = 11.5, 3.7 Hz, 0.67 H), 5.17 (dd, J = 11.5, 3.7 Hz, 0.33 H), 4.26–4.00 (m, 4.0 H), 3.38–3.31 (m, 1.0 H), 2.99–2.93 (m, 0.67 H), 2.74–2.67 (m, 0.33 H), 2.60–2.49 (m, 1.0 H), 2.44 (s, 1.0 H), 2.40 (s, 2.0 H), 2.36–2.21 (m, 2.0 H), 1.57 (s, 1.0 H), 1.56 (s, 2.0 H), 1.30–1.24 (m, 3.0 H), 1.23–1.16 (m, 3.0 H); 13C NMR (126 MHz, CDCl3): δc190.0, 189.9, 172.2, 172.1, 172.1, 171.9, 144.0, 143.5, 141.3, 140.6, 136.7, 136.4, 135.7, 135.0, 134.2, 133.6, 129.8, 129.7, 129.5, 129.0, 128.7, 128.7, 128.3, 128.1, 124.7, 124.1, 63.9, 61.8, 61.7, 61.5, 53.3, 53.1, 41.7, 40.4, 33.4, 32.7, 31.9, 29.7, 28.3, 21.8, 21.5, 21.1, 20.5, 14.0, 13.9, 13.9, 13.8; IR: ῡ = 1723, 1682, 1448, 1108, 911, 728 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H30NaO7S+, 509.1604, found 509.1601.
Dmethyl 2-((2-benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)methyl)malonate (5ac): Colorless oil (41.9 mg, 47% yield, dr = 2.0:1). 1H NMR (500 MHz, CDCl3): δH 8.15 (d, J = 7.7 Hz, 1.34 H), 8.08 (d, J = 7.7 Hz, 0.66 H), 7.82 (d, J = 7.7 Hz, 0.33 H), 7.77 (d, J = 7.7 Hz, 0.67 H), 7.67–7.61 (m, 1.0 H), 7.55–7.49 (m, 2.0 H), 7.32 (s, 0.33 H), 7.26–7.24 (m, 1.0 H), 7.17 (s, 0.67 H), 5.40 (dd, J = 10.7, 4.0 Hz, 0.67 H), 5.19 (dd, J = 10.7, 4.0 Hz, 0.33 H), 3.80 (s, 1.0 H), 3.76 (s, 2.0 H), 3.74 (s, 1.0 H), 3.71 (s, 2.0 H), 3.68–3.65 (m, 0.33 H), 3.52 (t, J = 7.3 Hz, 0.67 H), 3.25–3.18 (m, 1.0 H), 3.07–2.99 (m, 0.67 H), 2.80–2.73 (m, 0.67 H), 2.58–2.53 (m, 0.33 H), 2.52–2.47 (m, 0.67 H), 2.45 (s, 1.0 H), 2.42 (s, 2.0 H), 2.38–2.28 (m, 1.67 H); 13C NMR (126 MHz, CDCl3): δc 189.9 189.8, 169.3, 169.3, 169.0, 144.2, 143.7, 139.6, 136.4, 136.3, 135.1, 135.0, 134.4, 134.3, 129.7, 129.7, 129.6, 129.1, 128.8, 128.8, 128.4, 128.4, 124.7, 124.3, 63.6, 61.5, 52.9, 52.9, 52.9, 52.8, 49.6, 48.8, 34.8, 34.6, 34.5, 33.7, 30.3, 28.8, 21.8, 21.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C23H24NaO7S+, 467.1135, found 467.1119.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-phenylpropan-1-one (5af): Colorless oil (49.3 mg, 57% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.14 (d, J = 7.7 Hz, 1.2 H), 8.08 (d, J = 7.7 Hz, 0.8 H), 7.94 (d, J = 7.7 Hz, 0.8 H), 7.90 (d, J = 7.7 Hz, 1.2 H), 7.82 (d, J = 7.7 Hz, 0.4 H), 7.76 (d, J = 7.7 Hz, 0.6 H), 7.64–7.59 (m, 1.0 H), 7.55 (t, J = 7.7 Hz, 1.0 H), 7.52–7.48 (m, 2.0 H), 7.46–7.42 (m, 2.0 H), 7.32 (s, 0.4 H), 7.23–7.20 (m, 1.6 H), 5.45 (dd, J = 9.7, 3.7 Hz, 0.6 H), 5.24 (dd, J = 11.5, 3.7 Hz, 0.4 H), 3.40–3.31 (m, 1.0 H), 3.22–2.97 (m, 3.0 H), 2.56–2.43 (m, 1.2 H), 2.41 (s, 1.2 H), 2.38 (s, 1.8 H), 2.33–2.20 (m, 1.8 H); 13C NMR (126 MHz, CDCl3): δc 199.3, 199.1, 190.2, 190.0, 144.0, 143.6, 140.7, 139.9, 136.5, 136.5, 136.4, 136.3, 135.6, 134.8, 134.2, 133.3, 133.2, 129.6, 129.5, 129.5, 128.7, 128.7, 128.6, 128.6, 128.3, 128.2, 127.9, 127.9, 124.4, 124.1, 63.9, 61.6, 35.5, 35.3, 35.0, 34.2, 30.3, 29.1, 28.9, 28.7, 21.7, 21.5; IR: ῡ = 1679, 1596, 1447, 1298, 1133, 729 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H24NaO4S+, 455.1288, found 455.1264.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(4-methoxyphenyl)propan-1-one (5ag): Colorless oil (58.3 mg, 63% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.12 (d, J = 8.0 Hz, 1.2 H), 8.06 (d, J = 8.0 Hz, 0.8 H), 7.89 (d, J = 8.0 Hz, 0.8 H), 7.86 (d, J = 8.0 Hz, 1.2 H), 7.78 (d, J = 8.0 Hz, 0.4 H), 7.72 (d, J = 8.0 Hz, 0.6 H), 7.58 (q, J = 8.0 Hz, 1.0 H), 7.48–7.42 (m, 2.0 H), 7.30 (s, 0.6 H), 7.20–7.17 (m, 1.4 H), 6.90–6.86 (m, 2.0 H), 5.46 (dd, J = 10.0, 3.7 Hz, 0.6 H), 5.25 (dd, J = 11.5, 3.7 Hz, 0.4 H), 3.81 (s, 1.2 H), 3.81 (s, 1.8 H), 3.36–3.26 (m, 1.0 H), 3.12–2.91 (m, 2.6 H), 2.84–2.77 (m, 0.4 H), 2.55–2.40 (m, 1.4 H), 2.38 (s, 1.2 H), 2.36 (s, 1.8 H), 2.28–2.17 (m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 197.9, 197.7, 190.3, 190.2, 163.7, 163.6, 144.0, 143.6, 140.9, 140.1, 136.5, 135.7, 135.0, 134.3, 130.3, 130.3, 129.7, 129.6, 128.8, 128.7, 128.7, 128.5, 128.2, 124.4, 124.0, 113.8, 113.8, 64.0, 61.6, 55.5, 35.6, 35.3, 35.1, 33.9, 30.4, 29.4, 29.0, 28.9, 21.8, 21.6; IR: ῡ = 1652, 1595, 1571, 1294, 1134, 741 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C27H26NaO5S+, 485.1393, found 485.1387.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(p-tolyl)propan-1-one (5ah): Colorless oil (52.8 mg, 59% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.14 (d, J = 7.7 Hz, 1.2 H), 8.08 (d, J = 7.7 Hz, 0.8 H), 7.84–7.75 (m, 3.0 H), 7.64–7.59 (m, 1.0 H), 7.50 (t, J = 7.7 Hz, 1.0 H), 7.48 (t, J = 7.7 Hz, 1.0 H), 7.32 (s, 0.4 H), 7.24–7.20 (m, 3.6 H), 5.45 (dd, J = 9.7, 3.7 Hz, 0.6 H), 5.24 (dd, J = 11.5, 3.5 Hz, 0.4 H), 3.39–3.30 (m, 1.0 H), 3.18–2.95 (m, 2.6 H), 2.85–2.80 (m, 0.4 H), 2.56–2.43 (m, 1.4 H), 2.39 (s, 6.0 H), 2.30–2.19 (m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 198.9, 198.7, 190.2, 190.0, 144.1, 144.0, 144.0, 143.5, 140.7, 139.9, 136.4, 136.3, 135.6, 134.9, 134.2, 134.1, 134.1, 129.6, 129.5, 129.3, 129.3, 128.7, 128.7, 128.6, 128.3, 128.1, 128.1, 128.0, 124.4, 124.0, 63.9, 61.5, 35.4, 35.4, 35.0, 34.0, 30.3, 29.2, 28.9, 28.8, 21.7, 21.6, 21.5; IR: ῡ = 1674, 1604, 1448, 1299, 1134, 728 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C27H26NaO4S+, 469.1444, found 469.1420.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(3-methoxyphenyl)propan-1-one (5ai): Colorless oil (53.8 mg, 58% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.14 (d, J = 7.7 Hz, 1.2 H), 8.08 (d, J = 7.7 Hz, 0.8 H), 7.81 (d, J = 7.7 Hz, 0.4 H), 7.76 (d, J = 7.7 Hz, 0.6 H), 7.64–7.59 (m, 1.0 H), 7.52–7.47 (m, 3.0 H), 7.42 (s, 0.8 H), 7.36–7.32 (m, 1.6 H), 7.24–7.20 (m, 1.6 H), 7.10 (d, J = 7.7 Hz, 1.0 H), 5.44 (dd, J = 10.0, 4.0 Hz, 0.6 H), 5.24 (dd, J = 11.5, 4.0 Hz, 0.4 H), 3.84 (s, 1.2 H), 3.81 (s, 1.8 H), 3.39–3.30 (m, 1.0 H), 3.20–2.97 (m, 2.6 H), 2.85–2.80 (m, 0.4 H), 2.56–2.43 (m, 1.4 H), 2.41 (s, 1.2 H), 2.39 (s, 1.8 H), 2.31–2.21 (m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 199.1, 198.9, 190.2, 190.0, 159.8, 144.0, 143.6, 140.7, 139.9, 137.9, 137.9, 136.4, 136.3, 135.6, 134.9, 134.2, 129.6, 129.6, 129.5, 129.5, 128.7, 128.7, 128.6, 128.3, 128.2, 124.5, 124.1, 120.6, 120.5, 119.7, 119.6, 112.3, 112.2, 63.9, 61.6, 55.4, 55.4, 35.7, 35.4, 35.0, 34.4, 30.3, 29.3, 28.9, 28.8, 21.7, 21.5; IR: ῡ = 1679, 1596, 1448, 1260, 1135, 731 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C27H26NaO5S+, 485.1393, found 485.1388.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(3-chlorophenyl)propan-1-one (5aj): Colorless oil (61.8 mg, 66% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.13 (d, J = 8.0 Hz, 1.2 H), 8.08 (d, J = 8.0 Hz, 0.8 H), 7.91 (t, J = 1.7 Hz, 0.4 H), 7.87 (t, J = 1.7 Hz, 0.6 H), 7.83–7.76 (m, 2.0 H), 7.65–7.60 (m, 1.0 H), 7.53–7.47 (m, 3.0 H), 7.40–7.37 (m, 1.0 H), 7.30 (s, 0.4 H), 7.25–7.20 (m, 1.6 H), 5.43 (dd, J = 9.5, 4.0 Hz, 0.6 H), 5.24 (dd, J = 11.5, 4.0 Hz, 0.4 H), 3.40–3.32 (m, 1.0 H), 3.18–2.95 (m, 2.6 H), 2.88–2.80 (m, 0.4 H), 2.56–2.43 (m, 1.4 H), 2.42 (s, 1.2 H), 2.40 (s, 1.8 H), 2.34–2.21(m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 198.0, 197.8, 190.2, 189.9, 144.1, 143.7, 140.6, 139.8, 138.1, 138.1, 136.4, 136.3, 135.6, 135.0, 134.8, 134.3, 133.2, 133.1, 130.0, 130.0, 129.6, 129.5, 129.4, 128.7, 128.7, 128.7, 128.2, 128.2, 128.0, 128.0, 126.1, 126.0, 124.5, 124.2, 63.9, 61.7, 35.6, 35.2, 34.9, 34.3, 30.3, 29.1, 29.0, 28.6, 21.8, 21.6; IR: ῡ = 1682, 1596, 1448, 1298, 1134, 729 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H23ClNaO4S+, 489.0898, found 489.0885.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(2-methoxyphenyl)propan-1-one (5ak): Colorless oil (35.3 mg, 38% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.17 (d, J = 8.0 Hz, 1.2 H), 8.09 (d, J = 8.0 Hz, 0.8 H), 7.81 (d, J = 8.0 Hz, 0.4 H), 7.76 (d, J = 8.0 Hz, 0.6 H), 7.70 (dd, J = 8.0, 2.0 Hz, 0.4 H), 7.66–7.60 (m, 1.6 H), 7.54–7.44 (m, 3.0 H), 7.34 (s, 0.4 H), 7.24–7.20 (m, 1.6 H), 7.01–6.93 (m, 2.0 H), 5.45 (dd, J = 10.3, 3.7 Hz, 0.6 H), 5.22 (dd, J = 11.5, 4.0 Hz, 0.4 H), 3.90 (s, 1.2 H), 3.83 (s, 1.8 H), 3.36–3.25 (m, 1.0 H), 3.24–3.14 (m, 1.0 H), 3.10–2.99 (m, 1.6 H), 2.87–2.80 (m, 0.4 H), 2.57–2.43 (m, 1.4 H), 2.42 (s, 1.2 H), 2.40 (s, 1.8 H), 2.26–2.14 (m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 201.7, 201.4, 190.1, 190.1, 158.6, 158.5, 143.4, 140.8, 140.4, 136.4, 135.5, 135.0, 134.3, 134.2, 133.7, 133.7, 130.2, 129.7, 129.7, 129.5, 129.5, 128.7, 128.7, 128.6, 128.5, 128.4, 128.0, 127.8, 127.8, 124.3, 124.0, 120.7, 120.6, 111.6, 63.9, 61.5, 55.5, 55.5, 41.2, 39.7, 35.8, 30.3, 29.7, 29.5, 28.7, 21.8, 21.6; IR: ῡ = 1678, 1595, 1484, 1298, 1134, 729 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C27H26NaO5S+, 485.1393, found 485.1370.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(3,4-dichlorophenyl)propan-1-one (5al): Colorless oil (55.3 mg, 55% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.13 (d, J = 7.3 Hz, 1.2 H), 8.08 (d, J = 7.3 Hz, 0.8 H), 8.00 (d J = 2.0 Hz, 0.4 H), 7.97 (d, J = 2.0 Hz, 0.6 H), 7.82 (d, J = 8.0 Hz, 0.4 H), 7.76 (d, J = 8.0 Hz, 0.6 H), 7.74–7.71 (m, 1.0 H), 7.65–7.59 (m, 1.0 H), 7.53–7.47 (m, 3.0 H), 7.29 (s, 0.4 H), 7.23 (t, J = 8.0 Hz, 1.0 H), 7.19 (s, 0.6 H), 5.41 (dd, J = 9.0, 4.0 Hz, 0.6 H), 5.23 (dd, J = 11.5, 4.0 Hz, 0.4 H), 3.40–3.33 (m, 1.0 H), 3.14–2.94 (m, 2.6 H), 2.88–2.81 (m, 0.4 H), 2.55–2.44 (m, 1.4 H), 2.42 (s, 1.2 H), 2.40 (s, 1.8 H), 2.33–2.21(m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 197.0, 196.9, 190.2, 189.9, 144.1, 143.7, 140.5, 139.7, 137.9, 137.8, 136.4, 136.3, 136.1, 136.1, 135.7, 134.7, 134.3, 133.4, 133.4, 130.8, 130.7, 129.9, 129.6, 129.6, 129.4, 128.7, 128.7, 128.7, 128.3, 128.2, 127.1, 127.0, 124.6, 124.2, 63.8, 61.7, 35.5, 35.1, 34.9, 34.2, 30.2, 29.1, 28.9, 28.5, 21.8, 21.6; IR: ῡ = 1682, 1596, 1448, 1298, 1133, 726 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C26H22Cl2NaO4S+, 523.0508, found 523.0516.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-(thiophen-2-yl)propan-1-one (5am): Colorless oil (36.9 mg, 42% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.15 (d, J = 8.0 Hz, 1.2 H), 8.10 (d, J = 8.0 Hz, 0.8 H), 7.83 (d, J = 8.0 Hz, 0.4 H), 7.78 (d, J = 8.0 Hz, 0.6 H), 7.70 (dd, J = 10.3, 3.7 Hz, 1.0 H), 7.66–7.60 (m, 2.0 H), 7.54–7.49 (m, 2.0 H), 7.33 (s, 0.4 H), 7.25–7.22 (m, 1.0 H), 7.21 (s, 0.6 H), 7.12 (t, J = 4.3 Hz, 1.0 H), 5.42 (dd, J = 10.5, 4.0 Hz, 0.6 H), 5.23 (dd, J = 10.5, 4.0 Hz, 0.4 H), 3.41–3.34 (m, 1.0 H), 3.15–2.95 (m, 2.6 H), 2.90–2.83 (m, 0.4 H), 2.58–2.45 (m, 1.4 H), 2.43 (s, 1.2 H), 2.40 (s, 1.8 H), 2.35–2.23 (m, 1.6 H); 13C NMR (126 MHz, CDCl3): δc 192.2, 191.9, 190.2, 190.0, 144.1, 143.9, 143.8, 143.7, 140.6, 139.8, 136.4, 136.4, 135.6, 134.8, 134.3, 133.9, 133.8, 132.1, 132.0, 129.6, 129.6, 129.5, 128.8, 128.8, 128.7, 128.4, 128.3, 128.2, 124.6, 124.2, 63.9, 61.7, 36.2, 35.3, 35.0, 34.9, 30.3, 29.7, 29.5, 29.1, 21.8, 21.6; IR: ῡ = 1658, 1595, 1415, 1297, 1129, 725 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H22NaO4S2+, 461.0852, found 461.0874.
3-(2-Benzoyl-6-methyl-1,1-dioxidothiochroman-4-yl)-1-cyclopropylpropan-1-one (5an): Colorless oil (24.7 mg, 31% yield, dr = 1.5:1). 1H NMR (500 MHz, CDCl3): δH 8.15 (d, J = 7.3 Hz, 1.2 H), 8.09 (d, J = 7.3 Hz, 0.8 H), 7.82 (d, J = 8.0 Hz, 0.4 H), 7.76 (d, J = 8.0 Hz, 0.6 H), 7.66–7.61 (m, 1.0 H), 7.54–7.49 (m, 2.0 H), 7.28 (s, 0.4 H), 7.25–7.21 (m, 1.0 H), 7.17 (s, 0.6 H), 5.40 (dd, J = 10.0, 4.0 Hz, 0.6 H), 5.21 (dd, J = 11.5, 4.0 Hz, 0.4 H), 3.30–3.21 (m, 1.0 H), 3.00–2.95 (m, 0.4 H), 2.81–2.62 (m, 2.6 H), 2.51–2.45 (m, 0.4 H), 2.43 (s, 1.2 H), 2.41 (s, 1.8 H), 2.39–2.32 (m, 1.6 H), 2.17–2.07 (m, 1.0 H), 1.94–1.89 (m, 1.0 H), 1.03–0.95 (m, 2.0 H), 0.90–0.85 (m, 2.0 H); 13C NMR (126 MHz, CDCl3): δc 210.0, 209.8, 190.2, 190.0, 144.0, 143.5, 140.6, 139.9, 136.4, 136.4, 135.6, 134.9, 134.3, 129.6, 129.6, 129.5, 128.7, 128.7, 128.7, 128.3, 128.2, 124.5, 124.1, 63.9, 61.6, 40.6, 39.2, 35.4, 35.0, 30.3, 29.7, 28.9, 28.5, 21.8, 21.6, 20.7, 20.7, 11.1, 11.0, 11.0, 10.9; IR: ῡ = 1682, 1596, 1448, 1300, 1134, 728 cm1; HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C23H24NaO4S+, 419.1288, found 419.1268.

4. Conclusions

In summary, we have developed a photoredox-assisted intermolecular radical cascade cyclization reaction with α-carbonyl alkyl bromide 2 for the facile synthesis of diverse organosulfones. This innovative photocatalytic approach has garnered significant interest owing to its straightforward operation, remarkable compatibility with various functional groups, and impressive yields under mild reaction conditions. We are confident that this strategy will discover extensive utility in the realm of organic synthesis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29091971/s1, Table S1. Optimization of the reaction conditions. References [17,18,28,29,30,31,32,33,34,35] are cited in the Supplementary Materials.

Author Contributions

Conceptualization, F.G. and H.-L.H.; methodology, H.-L.H.; formal analysis, S.L. and Y.-Z.L.; investigation, Y.-Q.S.; data curation, T.-T.P.; writing—original draft preparation, F.G. and R.-F.Z.; writing—review and editing, W.H. and J.Y. All authors have read and agreed to the published version of the manuscript.

Funding

The National Natural Science Foundation of Shanghai (No. 21ZR1422600), China NSFC (Nos. 2210070260 and 21901097), the Natural Science Foundation of Shandong Province (ZR2022MB046), the Doctoral Program of Liaocheng University (318051516) and Introduction and Cultivation Program for Young Innovative Talents in Shandong Provincial Colleges and Universities (Innovation Team of Functional Organometallic Materials Presided by Prof. Yanlan Wang).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data generated or analyzed during this study are included in this published article and its Supplementary Information Files.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Huang, M.; Tang, M.; Hu, J.; Westcott, S.A.; Radius, U.; Marder, T.B. Cu-mediated vs. Cu-free Selective Borylation of Aryl Alkyl Sulfones. Chem. Commun. 2022, 58, 395–398. [Google Scholar]
  2. Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.; Gamba, A.; Murmann, W. Derivatives of Imidazole. I. Synthesis and Reactions of Imidazo[1,2-α]pyridines with Analgesic, Antiinflammatory, Antipyretic, and Anticonvulsant Activity. J. Med. Chem. 1965, 8, 305–312. [Google Scholar] [CrossRef] [PubMed]
  3. Jia, X.; Huang, C.; Zhang, X.; Lian, Z. Metal-free Sulfonylative Annulations of Alkyl Diiodides with Sulfur Dioxide: Synthesis of Cyclic Aliphatic Sulfones. Org. Chem. Front. 2021, 8, 5310–5315. [Google Scholar] [CrossRef]
  4. Dong, J.; Krasnova, L.; Finn, M.G.; Sharpless, K.B. Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angew. Chem. Int. Ed. 2014, 53, 9430–9448. [Google Scholar] [CrossRef] [PubMed]
  5. Parisi, G.; Degennaro, L.; Carlucci, C.; Candia, M.; Mastrorilli, P.; Roller, A.; Holzer, W.; Altomare, C.D.; Pace, V.; Luisi, R. A Greener and Efficient Access to Substituted Fourand Six-membered Sulfur-bearing Heterocycles. Org. Biomol. Chem. 2017, 15, 5000–5015. [Google Scholar] [CrossRef] [PubMed]
  6. Bowen, E.; Laidlaw, G.; Atkinson, B.C.; McArdle-Ismaguilov, T.A.; Franckevičius, V. Catalytic Enantioselective Synthesis of α Difunctionalized Cyclic Sulfones. J. Org. Chem. 2022, 87, 10256–10276. [Google Scholar] [CrossRef] [PubMed]
  7. Leucht, S.; Pitschel-Walz, G.; Engel, R.R.; Kissling, W. Amisulpride, an Unusual “Atypical” Antipsychotic: A Meta-Analysis of Randomized Controlled Trials. Am. J. Psychiatry 2002, 159, 180–190. [Google Scholar] [CrossRef]
  8. Grigalunas, M.; Ankner, T.; Norrby, P.-O.; Wiest, O.; Helquist, P. Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions: Catalyst Identification and Optimization. J. Am. Chem. Soc. 2015, 137, 7019–7022. [Google Scholar] [CrossRef]
  9. Nambo, M.; Crudden, C.M. Transition Metal-Catalyzed Cross-Couplings of Benzylic Sulfone Derivatives. Chem. Rec. 2021, 21, 3978–3989. [Google Scholar] [CrossRef]
  10. Gharpure, S.J.; Fartade, D.J.; Nanda, S.K.; Somani, S. Hydroalkoxylation-Initiated Cascade on Sulfone-Tethered Aryl Alkynols Gives Cyclic and Spiro-Heterocyclic β Ketosulfones. Org. Lett. 2023, 25, 6155–6160. [Google Scholar] [CrossRef]
  11. Bohl, C.E.; Gao, W.; Miller, D.D.; Bell, C.E.; Dalton, J.T. Structural Basis for Antagonism and Resistance of Bicalutamide in Prostate Cancer. Proc. Natl. Acad. Sci. USA 2005, 102, 6201–6206. [Google Scholar] [CrossRef] [PubMed]
  12. McCormack, P.L.; Keating, G.M. A Review of its Use in the Acute Treatment of Migraine. Drugs 2006, 66, 1129–1149. [Google Scholar] [CrossRef] [PubMed]
  13. Giannetti, A.M.; Wong, H.; Dijkgraaf, G.J.P.; Dueber, E.C.; Ortwine, D.F.; Bravo, B.J.; Gould, S.E.; Plise, E.G.; Lum, B.L.; Malhi, V.; et al. Identification, Characterization, and Implications of Species-Dependent Plasma Protein Binding for the Oral Hedgehog Pathway Inhibitor Vismodegib (GDC-0449). J. Med. Chem. 2011, 54, 2592–2601. [Google Scholar] [CrossRef] [PubMed]
  14. Jacob, C. A Scent of Therapy: Pharmacological Implications of Natural Products Containing Redox-active Sulfur Atoms. Nat. Prod. Rep. 2006, 23, 851–863. [Google Scholar] [CrossRef] [PubMed]
  15. Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu, W.; Jiang, H. Copper-Catalyzed Coupling of Oxime Acetates with Sodium Sulfinates: An Efficient Synthesis of Sulfone Derivatives. Angew. Chem., Int. Ed. 2014, 53, 4205–4208. [Google Scholar] [CrossRef]
  16. Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Bi(OTf)3-Mediated Cycloisomerization of γ-Alkynyl Arylketones: Application to the Synthesis of Substituted Furans. Org. Lett. 2015, 17, 1264–1267. [Google Scholar] [CrossRef] [PubMed]
  17. Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. One-Pot Access to Sulfonylmethyl Arylpyrroles via the Domino Aerobic Wacker-Type Aminocyclization/1,4-Sulfonyl Migration. Org. Lett. 2014, 16, 6252–6255. [Google Scholar] [CrossRef] [PubMed]
  18. Chang, M.-Y.; Cheng, Y.-C. Bi(OTf)3 Mediated exo-Olefin Isomerization of α-Benzoyl-β-Styrylsulfones. Org. Lett. 2015, 17, 5702–5705. [Google Scholar] [CrossRef] [PubMed]
  19. Kiren, S.; Padwa, A. A Benzannulation Protocol to Prepare Substituted Aryl Amines Using a Michael-Aldol Reaction of β-Keto Sulfones. J. Org. Chem. 2009, 74, 7781–7789. [Google Scholar] [CrossRef]
  20. Devi Laishram, R.; Chen, J.; Fan, B. Progress in Visible Light-Induced Difluroalkylation of Olefins. Chem. Rec. 2021, 21, 69–86. [Google Scholar] [CrossRef]
  21. Liao, J.; Yang, X.; Ouyang, L.; Lai, Y.; Huang, J.; Luo, R. Recent Advances in Cascade Radical Cyclization of Radical Acceptors for the Synthesis of Carbo- and Heterocycles. Org. Chem. Front. 2021, 8, 1345–1363. [Google Scholar] [CrossRef]
  22. Davies, J.; Sheikh, N.S.; Leonori, D. Photoredox Imino Functionalizations of Olefins. Angew. Chem. Int. Ed. 2017, 56, 13361–13365. [Google Scholar] [CrossRef] [PubMed]
  23. Li, J.-L.; Yang, S.-L.; Dai, Q.-S.; Yang, H.; Jiang, L.; Li, Q.-Z.; Wang, Q.-W.; Zhang, X.; Han, B. Modular Synthesis of 1,4-Diketones through Regioselective Bis-acylation of Olefins by Merging NHC and Photoredox Catalysis. Chinese. Chem. Lett. 2023, 34, 108271–108276. [Google Scholar] [CrossRef]
  24. Miyu Furuta, K.I.; Tokuyama, H. Photoredox-Catalyzed Intramolecular Cyclopropanation of Alkenes with α-Bromo-β-Keto esters. Org. Biomol. Chem. 2021, 19, 9172–9176. [Google Scholar]
  25. Fischer, D.M.; Lindner, H.; Amberg, W.H.; Carreira, E.M. Intermolecular Organophotocatalytic Cyclopropanation of Unactivated Olefins. J. Am. Chem. Soc. 2023, 145, 774–780. [Google Scholar] [CrossRef] [PubMed]
  26. Huang, H.-L.; Xu, J.; Fan, Y.-X.; Su, Q.-Q.; Du, J.-Y.; Zhang, R.-F.; Wang, Y.-l.; Hu, H.; Gao, F. Visible-Light-Induced Difunctionalization of Alkenyl Ketones with α-Carbonyl Alkyl Bromide: Concomitant Installation of C-C Bonds. J. Org. Chem. 2022, 87, 14093–14102. [Google Scholar] [CrossRef]
  27. Nguyen, J.D.; Tucker, J.W.; Konieczynska, M.D.; Stephenson, C.R.J. Intermolecular Atom Transfer Radical Addition to Olefins Mediated by Oxidative Quenching of Photoredox Catalysts. J. Am. Chem. Soc. 2011, 133, 4160–4163. [Google Scholar] [CrossRef]
  28. Chang, M.-Y.; Hsiao, Y.-T. H2SO4-Mediated Stereocontrolled Annulation of Oxygenated Naphthalenes and 4-Alkenols: One-Pot Synthesis of Tetanthrenes. J. Org. Chem. 2017, 82, 11594–11602. [Google Scholar] [CrossRef] [PubMed]
  29. Fang, Y.; Xu, D.; Yu, Y.; Tang, R.; Dai, S.; Wang, Z.; Zhang, W. Controlled Synthesis of β-Keto Sulfones and Vinyl Sulfones under Electrochemical Oxidation. Eur. J. Org. Chem. 2022, 2022, e202200091. [Google Scholar]
  30. Liu, S.; Chen, R.; Zhang, J. Copper-Catalyzed Redox Coupling of Nitroarenes with Sodium Sulfinates. Molecules 2019, 24, 1407. [Google Scholar] [CrossRef]
  31. Reddy, R.J.; Kumari, A.H.; Kumar, J.J. Recent Advances in the Synthesis and Applications of β-Keto Sulfones: New Prospects for the Synthesis of β-Keto Thiosulfones. Org. Biomol. Chem. 2021, 19, 3087–3118. [Google Scholar] [CrossRef] [PubMed]
  32. Chang, M.-Y.; Chen, H.-Y.; Chen, Y.-H. Synthesis of 2-Aryl-3-sulfonylchromans via Knoevenagel Condensation and Reduction Protocol. J. Org. Chem. 2017, 82, 12631–12639. [Google Scholar] [CrossRef] [PubMed]
  33. Chang, M.-Y.; Lai, K.-X.; Chang, Y.-L. In(OTf)3-Catalyzed Intramolecular Hydroarylation of α-Phenylallyl β-Ketosulfones-Synthesis of Sulfonyl 1-Benzosuberones and 1-Tetralones. RSC Adv. 2020, 10, 18231–18244. [Google Scholar] [CrossRef] [PubMed]
  34. Hsueh, N.-C.; Hsiao, Y.-T.; Chang, M.-Y. CuI Mediated Synthesis of Sulfonyl Dihydrofurans. Tetrahedron 2017, 73, 4398–4406. [Google Scholar] [CrossRef]
  35. Chang, M.-Y.; Cheng, Y.-C.; Chan, C.-K. Synthesis of Vinylcyclopropanes by Allylation/ring-closing Metathesis/Claisen Rearrangement. Tetrahedron 2014, 70, 8908–8913. [Google Scholar] [CrossRef]
Figure 1. (A,B) Functionalization of α-benzoyl β-styrylsulfones.
Figure 1. (A,B) Functionalization of α-benzoyl β-styrylsulfones.
Molecules 29 01971 g001
Scheme 1. Scope of substrate 1 for synthesizing tetracyclic products 3. Reaction conditions: 1a (0.2 mmol, 0.4 M in chlorobenzene), 2a (2.0 equiv.), LiBF4 (2.0 equiv.), base (5.0 equiv.), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere irradiated using blue LEDs (5W) at room temperature for 53 h, isolated yield, the dr value of 3 is 2.0:1.
Scheme 1. Scope of substrate 1 for synthesizing tetracyclic products 3. Reaction conditions: 1a (0.2 mmol, 0.4 M in chlorobenzene), 2a (2.0 equiv.), LiBF4 (2.0 equiv.), base (5.0 equiv.), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere irradiated using blue LEDs (5W) at room temperature for 53 h, isolated yield, the dr value of 3 is 2.0:1.
Molecules 29 01971 sch001
Scheme 2. Scope of substrate 2 for hexacyclic products 5. Reaction conditions: 1a (0.2 mmol, 0.1 M in dry DMF), 2a (2.0 equiv.), base (2.0 equiv.), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere irradiated using blue LEDs (5W) at room temperature for 24 h, isolated yield, dr = 1.5:1.
Scheme 2. Scope of substrate 2 for hexacyclic products 5. Reaction conditions: 1a (0.2 mmol, 0.1 M in dry DMF), 2a (2.0 equiv.), base (2.0 equiv.), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere irradiated using blue LEDs (5W) at room temperature for 24 h, isolated yield, dr = 1.5:1.
Molecules 29 01971 sch002
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
Molecules 29 01971 sch003
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 29 01971 i001
EntryPhotocatalystBaseAdditiveSolventYield of (%) b
3a3a′
1fac-Ir(ppy)32,6-lutidine-DMF1632
2fac-Ir(ppy)32,6-lutidine-1,4-Dioxane2345
3fac-Ir(ppy)32,6-lutidine-CHCl32550
4fac-Ir(ppy)32,6-lutidine-DMSO2142
5fac-Ir(ppy)32,6-lutidine-Methylbenzene2651
6fac-Ir(ppy)32,6-lutidine-Chlorobenzene2754
7fac-Ir(ppy)32,6-lutidine-Acetone2244
8fac-Ir(ppy)32,6-lutidine-o-DCB1122
9fac-Ir(ppy)3K2HPO4-Chlorobenzene2040
10 cfac-Ir(ppy)3--ChlorobenzeneTrace0
11fac-Ir(ppy)3K2CO3-ChlorobenzeneTrace0
13fac-Ir(ppy)3KHCO3-Chlorobenzene1836
14 dfac-Ir(ppy)32,6-lutidine-Chlorobenzene3263
15 efac-Ir(ppy)32,6-lutidineLiBF4 (2.0 equiv.)Chlorobenzene3640
16 ffac-Ir(ppy)32,6-lutidineLiBF4 (2.0 equiv.)Chlorobenzene4127
17 gfac-Ir(ppy)32,6-lutidineLiBF4 (2.0 equiv.)Chlorobenzene4828
18 hfac-Ir(ppy)32,6-lutidineLiBF4 (2.0 equiv.)Chlorobenzene3726
19 ifac-Ir(ppy)32,6-lutidineLiBF4 (2.0 equiv.)ChlorobenzeneTrace0
20 jfac-Ir(ppy)32,6-lutidineLiBF4 (2.0 equiv.)ChlorobenzeneN.R.0
21 k2,6-lutidineLiBF4 (2.0 equiv.)Chlorobenzene00
a Reaction conditions: 1a (0.2 mmol, 0.4 M in solvent), 2a (2.0 equiv.), LiBF4 (2.0 equiv.), base (5.0 equiv.), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere irradiated using blue LEDs (5W) at room temperature for 53 h. b Isolated yield of 3a. c Without base. d chlorobenzene (2.0 mL), 2,6-lutidine (3.0 eq). e chlorobenzene (2.0 mL), 2,6-lutidine (3.0 eq). f chlorobenzene (0.5 mL), 2,6-lutidine (3.0 eq). g chlorobenzene (0.5 mL), 2,6-lutidine (5.0 eq). h chlorobenzene (0.5 mL), 2,6-lutidine (7.0 eq). i In the air. j In the dark. k Without catalyst.
Table 2. Scope of substrate 1 for six-membered ring products 4 a,b.
Table 2. Scope of substrate 1 for six-membered ring products 4 a,b.
Molecules 29 01971 i002
EntryCompound 1, Ar1 =, Ar2 =Yield (%) b
1Ar1 = Ph, Ar2 = 4-MeC6H44a, 67%
2Ar1 = Ph, Ar2 = 4-tBuC6H44b, 48%
3Ar1 = Ph, Ar2 = 4-MeOC6H44c, 61%
4Ar1 = Ph, Ar2 = 4-BrC6H44d, 35%
5Ar1 = Ph, Ar2 = Ph4e, 40%
6Ar1 = Ph, Ar2 = 2-MeC6H44f, 34%
7Ar1 = Ph, Ar2 = 3-MeC6H44g, 43%
8Ar1 = 4-MeC6H4, Ar2 = 4-MeC6H44h, 68%
9Ar1 = 4-MeOC6H4, Ar2 = 4-MeC6H44i, 62%
10Ar1 = 4-BrC6H4, Ar2 = 4-MeC6H44j, 33%
11Ar1 = 4-MeC6H4, Ar2 = 4-FC6H44k, 58%
12Ar1 = 4-MeOC6H4, Ar2 = 4-FC6H44l, 56%
13Ar1 = 4-MeOC6H4, Ar2 = 4-BrC6H44m, 55%
14Ar1 = 4-FC6H4, Ar2 = 4-MeOC6H44n, 58%
15Ar1 = 4-BrC6H4, Ar2 = 4-MeOC6H44o, 29%
16Ar1 = 3-MeOC6H4, Ar2 = 4-FC6H44p, 29%
17Ar1 = 2-MeOC6H4, Ar2 = 4-FC6H44q, 54%
a Reaction conditions: 1a (0.2 mmol, 0.1 M in dry DMF), 2a (2.0 equiv.), base (2.0 equiv.), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere irradiated using blue LEDs (5W) at room temperature for 24 h. b Isolated yield, dr = 2.0:1.
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MDPI and ACS Style

Huang, H.-L.; Li, S.; Lv, Y.-Z.; Shi, Y.-Q.; Pang, T.-T.; Zhang, R.-F.; Huang, W.; Yin, J.; Gao, F. Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones. Molecules 2024, 29, 1971. https://doi.org/10.3390/molecules29091971

AMA Style

Huang H-L, Li S, Lv Y-Z, Shi Y-Q, Pang T-T, Zhang R-F, Huang W, Yin J, Gao F. Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones. Molecules. 2024; 29(9):1971. https://doi.org/10.3390/molecules29091971

Chicago/Turabian Style

Huang, Hong-Li, Shan Li, Yong-Zheng Lv, Ya-Qian Shi, Tian-Tian Pang, Ru-Fen Zhang, Wenjing Huang, Jianhui Yin, and Fei Gao. 2024. "Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones" Molecules 29, no. 9: 1971. https://doi.org/10.3390/molecules29091971

APA Style

Huang, H. -L., Li, S., Lv, Y. -Z., Shi, Y. -Q., Pang, T. -T., Zhang, R. -F., Huang, W., Yin, J., & Gao, F. (2024). Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones. Molecules, 29(9), 1971. https://doi.org/10.3390/molecules29091971

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