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Article

Synthesis of Indenones via Persulfate Promoted Radical Alkylation/Cyclization of Biaryl Ynones with 1,4-Dihydropyridines

by
Wanwan Wang
* and
Lei Yu
Jiangsu Key Laboratory of Chiral Pharmaceuticals Biosynthesis, Taizhou University, Taizhou 225300, China
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(2), 458; https://doi.org/10.3390/molecules29020458
Submission received: 24 December 2023 / Revised: 13 January 2024 / Accepted: 15 January 2024 / Published: 17 January 2024
(This article belongs to the Section Organic Chemistry)
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Abstract

:
The oxidative radical cascade cyclization of alkynes has emerged as a versatile strategy for the efficient construction of diverse structural units and complex molecules in organic chemistry. This work reports an alkyl radical initiated 5-exo-trig cyclization of biaryl ynones with 1,4-dihydropyridines to selectively synthesize indenones.

1. Introduction

Indenones are attracting increasing attention in organic synthesis, as these derivatives are widely used in biological molecules, pharmaceuticals and functional materials [1,2,3]. As a result, considerable effort has been dedicated to developing efficient and novel methods for accessing functionalized indenones [4,5]. The radical cascade reaction provides an efficient method for rapidly increasing the complexity of molecules to obtain indenones [4].
Alkynes are a diverse functional group widely present in organics. The radical induced cascade reactions of alkynes are a useful and efficient method for rapidly accessing complex molecules, and they have therefore attracted considerable attention [6,7,8,9,10]. The direct difunctionalization of alkyne feedstocks has developed rapidly due to its atom and step economy. Therefore, numerous methods have been established to synthesize functionalized molecules in recent years. In addition, radical cascade reactions involving the 1,2-difunctionalization of alkyne have become a versatile tool in contemporary organic chemistry [11,12,13,14]. To date, the cyclization of alkynes toward the synthesis of cyclic compounds has been effectively investigated [15,16,17,18,19,20,21,22,23,24,25,26]. Recently, the radical cascade cyclization of biaryl ynones has been demonstrated to be a useful approach to construct six-membered spiro[5,5]trienones [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42] with the development of different types of radical precursors (Scheme 1a–c). For example, Chen and Zhou reported an iron-catalyzed cascade silyl radical addition/6-exo-trig cyclization/dearomatization of biaryl ynones with silane, affording silylated spiro[5.5]trienones in good yields [35]. In addition, several groups have demonstrated some elegant examples based on C-, N-, P-, S-, Si-, Se-centered radicals-induced cascade cyclization of biaryl ynones in the presence of transition-metal catalysts, oxidants or photocatalysts [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. For example, Duan and Yang reported the preparation of alkyl-functional spiro[5.5]trienone through alkylative dearomatization and the spirocyclization of biaryl ynones, respectively [29,33]. Later, Yang’s group further explored this reaction using 4-alkyl-1,4-dihydropyridines (DHPs) as radical precursors under an irradiation of visible light [32]. Although several groups have applied this radical cascade strategy to prepare alkyl-functional spiro[5.5]trienone, 5-exo-trig cascade reactions of biaryl ynones and alkyl radical precursors toward indenones are surprisingly rarely explored due to the chemo- and regio-selective issues of the highly reactive vinyl radical species [43]. Inspired by these works, we believe that the control of the selective cyclization sites of the electron-poor alkylated vinyl radical intermediates is interesting and still in great demand, especially those triggered by the same alkyl radical precursors. Herein, we would like to report our efforts to put this concept into practice, using 4-alkyl-DHPs as alkyl radical precursors in the presence of Na2S2O8 (Scheme 1d).

2. Results and Discussion

The study commenced with the reaction of biaryl ynone (1a) and 4-cyclohexyl-DHP (2a) under visible light irradiation conditions. In the presence of Na2S2O8 (2 equiv), the reaction was performed in acetone at 60 °C for 12 h (Table 1, entry 1). The five-membered indenone was obtained in a yield of 39%, which was a pleasing result. To improve the yield, we screened different solvents and found that using MeCN or AcOEt instead of acetone increased the yield (Table 1, entries 2–3). Notably, the reaction efficiency for the generation of indenone 3a was significantly higher when using MeCN-H2O mixed solvents compared to single solvents (Table 1, entries 4–7). This may be due to the appropriate solubility providing necessary medium substances, which assisted the diffusion and interaction of reactants in the mixed solvents. The effect of different oxidants on this cascade reaction was also explored. When the oxidant Na2S2O8 was changed to K2S2O8, (NH4)2S2O8, TBHP or DTBP, the reaction was either inhibited or resulted in lower yields of 3a (Table 1, entries 8–11). Meanwhile, the yield did not improve significantly when the reaction temperature was increased or decreased (Table 1, entries 12 and 13). Prolonging the reaction time did not achieve better results (Table 1, entry 14). No product was detected when the reaction was performed without the oxidant Na2S2O8 (Table 1, entry 15).
With the optimized reaction conditions, we set out to investigate the generality of this nucleophilic C-centered radical-induced cyclization of biaryl ynones with 4-cyclohexyl-DHP for the construction of 5-membered indenones (Scheme 2). To begin with, we examined the scope and limitation of biaryl ynones in this reaction. A variety of monosubstituted group on Ar ring (1b–1i) reacted well with 4-cyclohexyl-DHP to give the corresponding indenones 3b–3i in yields ranging from 60% to 85%. For example, halogen substituents (−F, −Cl and −Br) on the Ar ring were well tolerated, providing opportunities for further synthetic transformations of products. Moreover, disubstituted phenyl ring 1j–1l also successfully participated in the reaction, affording the target products (3j–3l) in 63–71% yields. Next, the reaction scope with different substituents on the Ar1 ring was investigated. The Ar1 ring without any substitutions was also compatible in the annulation system. Importantly, no matter whether the Ar1 ring in biaryl ynones was modified with either one or two groups, all of them could undergo the cascade alkylation reaction, generating the desired products (3m–3s) in yields ranging from 61% to 76%.
Next, we moved to assess the generality of the cyclization with different groups on the Ar2 ring in biaryl ynones as well as various nucleophilic C-centered radical precursors. As shown in Scheme 3, the reaction tolerated substitution around the Ar2 ring well, including methyl, halogens, and methoxy. For example, substrate 1v reacted with 4-cyclohexyl-DHP well to give product 3v in 62% yield. Furthermore, we also tested another 4-alkyl-DHP in this nucleophilic C-centered radical-induced cyclization. There was good tolerance of secondary alkyl-substituted DHP. The reaction proceeded smoothly under the standard conditions when using the bulky DHP as the substrate, yielding the desired product 3z in a lower yield. Finally, 3a was definitely confirmed by X-ray crystallography (CCDC 2306682).
Preliminary experiments were conducted to gain insight into this radical cascade reaction mechanism. The alkylation reaction was almost completely inhibited when the radical-trapping reagent TEMPO was added (Scheme 4a and Supporting Information S2). During the process, the alkyl radical intermediate was captured by TEMPO, and its corresponding adduct is detected by HR-MS analysis. Based on recent studies on S2O82− salt-promoted cascade alkylation [44,45,46] and the above experimental results, we proposed a possible mechanism for this alkyl-centered radical-initiated cyclization transformation of alkynes (Scheme 4b). Initially, S2O82− salt oxidized 4-cyclohexyl-DHP to generate cyclohexyl radical A and cation E, which reacted with sulfate anions to give a pyridine derivative. For the 5-exo-trig cyclization, the cyclohexyl radical A was trapped by C–C triple bonds to afford vinyl radical B, which subsequently underwent 5-exo-trig cyclization to obtain intermediate C. The above-mentioned intermediate C was oxidized by S2O82− to provide carbocation D, which finally lost H+ to produce indenones 3a.
In summary, we report the synthesis of a series of five-membered indenones via the alkyl-centered radical-induced cyclization of biaryl ynones, using cheap Na2S2O8 as an oxidant. The unfavorable enthalpic and entropic factors and variable chemo-selectivity are the challenges of this cascade reaction. Key features of this approach include straightforward and simple operational procedures, good functional group tolerance, excellent chem- and regioselectivity, and wide substrate scope.

3. Materials and Methods

3.1. General Information

All reactions were carried out under air atmosphere. 1H NMR and 13C NMR spectra were measured on a Bruker Avance NMR spectrometer (600 MHz/151 MHz/565 NMR) in CDCl3 as solvent and recorded in ppm relative to internal tetramethylsilane standard. 1H NMR data are reported as follows: δ, chemical shift; coupling constants (J are given in Hertz, Hz) and integration. Abbreviations to denote the multiplicity of a particular signal were s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets) and m (multiplet).

3.2. Preparation of the Starting Materials

Biaryl ynone (1a) derivatives were prepared according to the reported method [29,30,31,32]. The solvents and oxidants including acetone, MeCN, K2S2O8, DTBP, etc. were purchased from commercial companies such as Energy Chemical (Shanghai), Shanghai Xianding Biotechnology Co., Ltd., etc. (Shanghai, China); petroleum ether and ethyl acetate were purchased from Shanghai Titan Technology Co., Ltd. (Shanghai, China). Products were purified by flash chromatography on 200–300 mesh silica gel.

3.3. General Procedure for the Synthesis of 3a

A 15 mL pressure tube was charged with biaryl ynone (1a, 0.2 mmol), 4-alkyl Hantzsch ester (2a, 0.4 mmol), Na2S2O8 (2 equiv, 0.4 mmol) in CH3CN/H2O (2 mL, v/v = 3:1), and a magnetic stir bar. The reaction mixture was stirred at 60 °C for 12 h (TLC tracking detection). After the reaction was finished, the mixture was diluted with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to yield the crude product, which was further purified by flash chromatography (silica gel, petroleum ether/ethyl acetate) to give the desired product 3a.

3.4. Characterization Data of Products

The chemical structural formulae and 1H NMR and 13C NMR spectra of the products 3a–3z can be seen in the Supporting Information S3 and S17.
2-Cyclohexyl-7-(4-methoxyphenyl)-3-phenyl-1H-inden-1-one (3a). The product was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3a as a yellow solid (61 mg, 78% yield), m.p.: 90.5–91.8 °C. 1H NMR (600 MHz, CDCl3) δ 7.54–7.47 (m, 4H), 7.47–7.43 (m, 1H), 7.40–7.35 (m, 2H), 7.25 (t, J = 3.8 Hz, 1H), 7.09 (dd, J = 7.9, 0.6 Hz, 1H), 7.01–6.95 (m, 2H), 6.81 (dd, J = 7.2, 0.6 Hz, 1H), 3.86 (s, 3H), 2.44 (tt, J = 12.1, 3.4 Hz, 1H), 1.81 (qd, J = 12.4, 2.9 Hz, 2H), 1.69 (d, J = 12.5 Hz, 2H), 1.59 (d, J = 10.1 Hz, 1H), 1.54 (s, 2H), 1.22–1.09 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.4, 159.6, 153.5, 147.0, 139.9, 139.1, 133.2, 132.6, 131.0, 130.4, 129.7, 128.7, 128.7, 128.0, 125.7, 119.2, 113.3, 55.2, 36.0, 31.0, 26.5, 25.7. HRMS (ESI) calcd for C28H26NaO2 [M + Na]+ 417.1830, found 417.1818.
2-Cyclohexyl-7-(4-methoxyphenyl)-3-(p-tolyl)-1H-inden-1-one (3b). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3b as a yellow solid (60 mg, 74% yield), m.p.: 112.6–114.1 °C. 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 7.2 Hz, 1H), 3.88–3.85 (m, 3H), 2.45 (s, 3H), 1.83 (dd, 2H), 1.69 (d, J = 12.7 Hz, 2H), 1.59 (d, J = 10.6 Hz, 1H), 1.53 (s, 1H), 1.26 (d, J = 9.2 Hz, 2H), 1.16 (dd, J = 22.1, 11.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 197.4, 159.6, 153.7, 147.0, 139.8, 138.9, 138.7, 132.5, 131.0, 130.4, 130.2, 129.7, 129.3, 128.0, 125.8, 119.2, 113.3, 55.2, 36.0, 31.0, 26.6, 25.7, 21.4. HRMS (ESI) calcd for C29H28NaO2 [M + Na]+ 431.1987, found 431.1974.
2-Cyclohexyl-3-(4-ethylphenyl)-7-(4-methoxyphenyl)-1H-inden-1-one (3c). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3c as a yellow solid (60 mg, 71% yield), m.p.: 97–98 °C. 1H NMR (600 MHz, CDCl3) δ 7.41 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.18 (d, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 7.2 Hz, 1H), 3.79 (s, 3H), 2.68 (q, J = 7.6 Hz, 2H), 2.39 (ddd, J = 12.1, 8.9, 3.4 Hz, 1H), 1.77 (dd, J = 23.5, 11.0 Hz, 2H), 1.63 (d, J = 12.4 Hz, 2H), 1.52 (d, J = 10.9 Hz, 1H), 1.46 (s, 1H), 1.25 (t, J = 7.6 Hz, 3H), 1.16–1.06 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 197.5, 159.6, 153.7, 147.0, 145.0, 139.8, 138.9, 132.5, 131.0, 130.4, 129.7, 128.1, 128.0, 125.9, 121.8, 119.3, 113.3, 55.2, 36.0, 30.9, 28.8, 26.6, 25.7, 15.3. HRMS (ESI) calcd for C30H30NaO2 [M + Na]+ 445.2143, found 445.2135.
3-(4-(tert-Butyl)phenyl)-2-cyclohexyl-7-(4-methoxyphenyl)-1H-inden-1-one (3d). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3d as a yellow solid (62 mg, 69% yield), m.p.: 107.1–108.3 °C. 1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.18 (t, J = 3.8 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 6.7 Hz, 1H), 3.79 (s, 3H), 2.44–2.37 (m, 1H), 1.80 (dd, 2H), 1.63 (d, J = 12.4 Hz, 2H), 1.52 (d, J = 9.8 Hz, 1H), 1.46 (s, 1H), 1.33 (s, 9H), 1.23–1.18 (m, 2H), 1.12–1.08 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 196.4, 158.5, 152.5, 150.8, 145.9, 138.7, 137.8, 131.4, 129.9, 129.4, 129.0, 128.7, 126.8, 124.9, 124.5, 118.4, 112.3, 54.2, 35.0, 33.8, 30.3, 29.9, 25.5, 24.7. HRMS (ESI) calcd for C32H34NaO2 [M + Na]+ 473.2457, found 473.2442.
2-Cyclohexyl-3-(4-fluorophenyl)-7-(4-methoxyphenyl)-1H-inden-1-one (3e). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3e as a yellow solid (49 mg, 60% yield), m.p.: 101.3–102.1 °C. 1H NMR (600 MHz, CDCl3) δ 7.43–7.40 (m, 2H), 7.30–7.28 (m, 2H), 7.20–7.19 (m, 1H), 7.14 (t, J = 8.6 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.93–6.90 (m, 2H), 6.71 (d, J = 6.8 Hz, 1H), 3.79 (s, 3H), 2.33 (tt, J = 12.1, 3.4 Hz, 1H), 1.75–1.69 (m, 2H), 1.63 (d, J = 12.4 Hz, 2H), 1.53 (d, J = 10.3 Hz, 1H), 1.46 (d, J = 13.3 Hz, 2H), 1.13–1.04 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.1, 162.8 (d, J = 248.6 Hz), 159.7, 152.5, 146.9, 140.0, 139.4, 132.6, 131.1, 130.4, 129.9 (d, J = 8.4 Hz), 129.5, 129.1 (d, J = 3.2 Hz), 125.6, 119.0, 115.9 (d, J = 21.4 Hz), 113.3, 55.2, 36.0, 31.0, 26.5, 25.7.
3-(4-Chlorophenyl)-2-cyclohexyl-7-(4-methoxyphenyl)-1H-inden-1-one (3f). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3f as a yellow solid (53 mg, 62% yield), m.p.: 97.6–98.5 °C. 1H NMR (600 MHz, CDCl3) δ 7.52–7.47 (m, 4H), 7.32 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 7.9, 0.7 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.77 (dd, J = 7.2, 0.6 Hz, 1H), 3.87 (s, 3H), 2.43–2.36 (m, 1H), 1.81–1.75 (m, 2H), 1.70 (d, J = 12.4 Hz, 2H), 1.60 (d, J = 10.0 Hz, 1H), 1.54 (d, 1H), 1.28–1.25 (m, 1H), 1.18–1.11 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.0, 159.7, 152.2, 146.7, 140.1, 139.6, 134.7, 132.7, 131.6, 131.2, 130.4, 129.5, 129.0, 125.5, 119.0, 113.3, 55.2, 36.1, 31.0, 26.5, 25.7. HRMS (ESI) calcd for C28H25ClNaO2 [M + Na]+ 451.1441, found 451.1429.
2-Cyclohexyl-7-(4-methoxyphenyl)-3-(m-tolyl)-1H-inden-1-one (3g). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3g as a yellow solid (54 mg, 66% yield), m.p.: 121.8–122.8 °C. 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 8.7 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.19 (dd, J = 8.1, 5.1 Hz, 2H), 7.13–7.09 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 5.8 Hz, 2H), 6.75 (d, J = 7.2 Hz, 1H), 3.79 (s, 3H), 2.40–2.34 (m, 4H), 1.78–1.71 (m, 2H), 1.62 (d, J = 12.4 Hz, 2H), 1.50 (s, 3H), 1.14–1.04 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.4, 159.6, 153.7, 147.1, 139.8, 139.0, 138.3, 133.1, 132.5, 131.0, 130.4, 129.7, 129.5, 128.5, 128.5, 125.8, 125.1, 119.3, 113.3, 55.2, 36.0, 31.0, 26.5, 25.7, 21.6. HRMS (ESI) calcd for C29H28NaO2 [M + Na]+ 431.1987, found 431.1977.
3-(3-Bromophenyl)-2-cyclohexyl-7-phenyl-1H-inden-1-one (3h). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3h as a yellow oil (53 mg, 60% yield). 1H NMR (600 MHz, CDCl3) δ 7.64–7.57 (m, 1H), 7.55–7.50 (m, 3H), 7.47–7.43 (m, 2H), 7.43–7.38 (m, 2H), 7.31–7.28 (m, 2H), 7.12 (dd, J = 7.8, 0.6 Hz, 1H), 6.82 (dd, J = 7.2, 0.6 Hz, 1H), 2.39 (tt, J = 12.1, 3.4 Hz, 1H), 1.81–1.73 (m, 2H), 1.70 (dd, J = 9.6, 2.3 Hz, 2H), 1.60 (d, J = 7.7 Hz, 1H), 1.54 (d, J = 13.6 Hz, 2H), 1.17 (q, J = 12.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 196.8, 151.9, 146.5, 140.4, 139.8, 137.3, 135.3, 132.8, 131.8, 131.2, 130.8, 130.3, 129.0, 128.2, 127.9, 126.7, 125.7, 122.8, 119.4, 36.1, 31.0, 26.5, 25.6. HRMS (ESI) calcd for C27H23BrNaO [M + Na]+ 465.0830, found 465.0819.
2-Cyclohexyl-3-(3,4-dimethylphenyl)-7-(4-methoxyphenyl)-1H-inden-1-one (3i). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3i as a yellow solid (53 mg, 63% yield), m.p.: 107.6–108.6 °C. 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.7 Hz, 2H), 7.17–7.10 (m, 3H), 7.00 (dd, J = 7.9, 0.6 Hz, 1H), 6.92 (d, J = 8.7 Hz, 3H), 6.41–6.36 (m, 1H), 3.79 (s, 3H), 2.30 (s, 3H), 2.20–2.14 (m, 1H), 2.10 (s, 3H), 1.58 (d, J = 9.2 Hz, 4H), 1.43 (d, J = 12.5 Hz, 2H), 1.27–1.17 (m, 2H), 1.04 (s, 2H). 13C NMR (151 MHz, CDCl3) δ 197.5, 159.6, 155.1, 147.7, 139.6, 139.4, 137.4, 134.1, 133.4, 132.8, 130.8, 130.4, 129.9, 129.6, 125.9, 125.7, 125.4, 119.2, 113.3, 55.2, 36.0, 30.9, 30.6, 26.5, 26.5, 25.7, 20.4, 17.1. HRMS (ESI) calcd for C30H30NaO2 [M + Na]+ 445.2143, found 445.2131.
2-Cyclohexyl-3-(2,3-dimethylphenyl)-7-(4-methoxyphenyl)-1H-inden-1-one (3j). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3j as a yellow solid (50 mg, 58% yield), m.p.: 111.4–112.4 °C. 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.6 Hz, 2H), 7.17–7.11 (m, 3H), 7.01 (d, J = 7.9 Hz, 1H), 6.95–6.88 (m, 3H), 6.39 (d, J = 7.1 Hz, 1H), 3.80 (s, 3H), 2.30 (s, 3H), 2.17 (dd, J = 13.5, 10.1 Hz, 1H), 2.10 (s, 3H), 1.58 (d, J = 9.1 Hz, 3H), 1.43 (d, J = 12.6 Hz, 4H), 1.04 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 197.5, 159.6, 155.1, 147.7, 139.6, 139.4, 137.4, 134.1, 133.4, 132.8, 130.8, 130.4, 129.9, 129.6, 125.9, 125.7, 125.4, 119.2, 113.3, 55.2, 36.0, 30.9, 30.6, 26.5, 26.5, 25.7, 20.4, 17.1. HRMS (ESI) calcd for C30H30NaO2 [M + Na]+ 445.2143, found 445.2136.
2-Cyclohexyl-3-(3,5-dimethylphenyl)-7-(4-methoxyphenyl)-1H-inden-1-one (3k). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3k as a yellow solid (60 mg, 71% yield), m.p.: 126.3–127.3 °C. 1H NMR (600 MHz, CDCl3) δ 7.43–7.39 (m, 2H), 7.18 (t, 1H), 7.01 (d, J = 7.3 Hz, 2H), 6.92–6.89 (m, 4H), 6.75 (d, J = 7.1 Hz, 1H), 3.79 (s, 3H), 2.39–2.36 (m, 1H), 2.33 (s, 6H), 1.79–1.72 (m, 2H), 1.62 (d, J = 12.5 Hz, 2H), 1.52 (d, J = 8.9 Hz, 1H), 1.46 (s, 2H), 1.13–1.05 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 196.5, 158.5, 152.9, 146.1, 138.7, 137.8, 137.1, 132.0, 131.5, 129.9, 129.3, 128.7, 124.7, 124.6, 118.3, 112.2, 54.2, 35.0, 29.9, 25.5, 24.7, 20.4. HRMS (ESI) calcd for C30H30NaO2 [M + Na]+ 445.2143, found 445.2133.
2-Cyclohexyl-3,7-diphenyl-1H-inden-1-one (3l). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford 3m as a yellow solid (50 mg, 68% yield), m.p.: 89.2–90.1 °C. 1H NMR (600 MHz, CDCl3) δ 7.44 (dd, J = 11.3, 4.4 Hz, 4H), 7.39–7.35 (m, 3H), 7.33–7.30 (m, 3H), 7.19 (t, 1H), 7.02 (dd, J = 7.8, 0.7 Hz, 1H), 6.77 (dd, J = 7.2, 0.6 Hz, 1H), 2.36 (tt, J = 12.1, 7.8, 3.4 Hz, 1H), 1.72 (qd, J = 12.2, 6.0 Hz, 2H), 1.61 (d, J = 12.4 Hz, 2H), 1.48 (t, J = 12.5 Hz, 3H), 1.12–1.04 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.2, 153.7, 147.0, 140.1, 139.2, 137.4, 133.2, 132.6, 131.0, 129.1, 128.8, 128.7, 128.1, 128.0, 127.9, 119.6, 36.0, 31.0, 26.6, 25.7.
2-Cyclohexyl-7-(4-ethoxyphenyl)-3-phenyl-1H-inden-1-one (3m). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3m as a yellow oil (62 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 7.55–7.43 (m, 5H), 7.40–7.35 (m, 2H), 7.25 (t, J = 3.8 Hz, 1H), 7.09 (dd, J = 7.9, 0.7 Hz, 1H), 7.00–6.95 (m, 2H), 6.80 (dd, J = 7.2, 0.7 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 2.44 (tt, J = 12.1, 3.4 Hz, 1H), 1.86–1.77 (m, 2H), 1.69 (d, J = 12.5 Hz, 2H), 1.59 (d, J = 8.9 Hz, 1H), 1.53 (s, 2H), 1.44 (t, J = 7.0 Hz, 3H), 1.20–1.10 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.3, 159.1, 153.5, 147.0, 140.0, 139.1, 133.2, 132.6, 131.0, 130.4, 129.6, 129.5, 128.7, 128.6, 128.0, 125.7, 119.2, 113.8, 63.4, 36.0, 31.0, 26.5, 25.7, 14.9. HRMS (ESI) calcd for C29H28NaO2 [M + Na]+ 431.1987, found 431.1971.
7-(3-Chlorophenyl)-2-cyclohexyl-3-phenyl-1H-inden-1-one (3n). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3n as a yellow oil (49 mg, 61% yield). 1H NMR (600 MHz, CDCl3) δ 7.52 (t, J = 7.4 Hz, 2H), 7.46 (d, J = 11.0 Hz, 2H), 7.42 (dd, J = 5.0, 2.0 Hz, 1H), 7.40–7.34 (m, 4H), 7.28 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 2.48–2.41 (m, 1H), 1.84–1.74 (m, 2H), 1.70 (d, J = 12.1 Hz, 2H), 1.59 (d, J = 9.8 Hz, 1H), 1.54 (s, 2H), 1.21–1.10 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.0, 153.8, 147.0, 139.3, 139.2, 138.4, 133.8, 133.0, 132.8, 130.6, 129.0, 128.9, 128.8, 128.7, 128.1, 128.0, 127.5, 126.1, 120.0, 36.0, 31.0, 26.5, 25.7. HRMS (ESI) calcd for C27H23ClNaO [M + Na]+ 421.1335, found 421.1324.
7-(3-Chloro-4-methoxyphenyl)-2-cyclohexyl-3-phenyl-1H-inden-1-one (3o). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3o as a yellow solid (53 mg, 62% yield), m.p.: 99.5–100.7 °C. 1H NMR (600 MHz, CDCl3) δ 7.54–7.50 (m, 3H), 7.48–7.45 (m, 2H), 7.40–7.37 (m, 2H), 7.26 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.85–6.82 (m, 1H), 3.96 (s, 3H), 2.44 (tt, J = 12.1, 3.4 Hz, 1H), 1.83–1.76 (m, 2H), 1.70 (d, J = 12.5 Hz, 2H), 1.55 (d, J = 13.4 Hz, 2H), 1.23–1.12 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 197.2, 154.9, 153.7, 147.1, 139.2, 138.4, 133.1, 132.7, 130.7, 130.6, 130.6, 128.9, 128.8, 128.7, 128.0, 125.9, 121.9, 119.7, 111.2, 56.1, 36.0, 31.0, 26.5, 25.7. HRMS (ESI) calcd for C28H25ClNaO2 [M + Na]+ 451.1441, found 451.1436.
2-Cyclohexyl-7-(4-methoxy-2-methylphenyl)-3-phenyl-1H-inden-1-one (3p). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3p as a yellow solid (60 mg, 73% yield), m.p.: 82.4–83.4 °C. 1H NMR (600 MHz, CDCl3) δ 7.52 (dd, J = 9.3, 5.5 Hz, 2H), 7.48–7.44 (m, 1H), 7.41–7.39 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.98–6.95 (m, 1H), 6.87–6.83 (m, 2H), 6.80 (dd, J = 8.3, 2.6 Hz, 1H), 3.84 (s, 3H), 2.42 (tt, J = 12.1, 3.4 Hz, 1H), 2.16 (s, 3H), 1.81–1.76 (m, 2H), 1.68 (d, J = 9.5 Hz, 2H), 1.53 (s, 2H), 1.25 (s, 2H), 1.14 (d, J = 9.9 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 197.5, 159.1, 153.7, 146.3, 139.1, 138.9, 137.2, 133.2, 132.3, 131.5, 130.3, 130.0, 128.7, 128.6, 128.0, 127.1, 119.3, 115.2, 110.8, 55.1, 35.9, 30.9, 26.5, 25.7, 20.4. HRMS (ESI) calcd for C29H28NaO2 [M + Na]+ 431.1987, found 431.1975.
2-Cyclohexyl-7-(4-methoxy-3-methylphenyl)-3-phenyl-1H-inden-1-one (3q). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3q as a yellow solid (57 mg, 70% yield), m.p.: 101.5–102.5 °C. 1H NMR (600 MHz, CDCl3) δ 7.52 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.42–7.35 (m, 3H), 7.29 (s, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 2.44 (tt, J = 12.1, 3.5 Hz, 1H), 2.29 (d, J = 5.3 Hz, 3H), 1.84–1.76 (m, 2H), 1.69 (d, J = 12.1 Hz, 2H), 1.60 (s, 1H), 1.54 (d, J = 13.4 Hz, 2H), 1.20–1.12 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.3, 157.8, 153.4, 147.0, 140.2, 139.1, 133.3, 132.5, 131.2, 131.1, 129.2, 128.7, 128.6, 128.1, 128.0, 126.0, 125.7, 119.1, 109.1, 55.3, 36.0, 31.0, 26.6, 25.7, 16.3. HRMS (ESI) calcd for C29H28NaO2 [M + Na]+ 431.1987, found 431.1975.
7-(4-Chloro-3-methylphenyl)-2-cyclohexyl-3-phenyl-1H-inden-1-one (3r). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3r as a yellow oil (50 mg, 61% yield). 1H NMR (600 MHz, CDCl3) δ 7.51 (t, J = 7.4 Hz, 2H), 7.46 (d, J = 7.3 Hz, 1H), 7.39–7.33 (m, 2H), 7.25–7.23 (m, 2H), 7.11–7.04 (m, 3H), 6.81 (d, J = 7.2 Hz, 1H), 2.47–2.41 (m, 1H), 2.38 (s, 3H), 1.78 (dt, J = 22.0, 7.7 Hz, 2H), 1.70–1.68 (m, 2H), 1.59–1.53 (m, 3H), 1.20–1.13 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.0, 153.5, 146.9, 140.4, 139.1, 137.5, 137.2, 133.3, 132.4, 131.1, 129.7, 128.7, 128.6, 128.0, 126.8, 126.0, 119.4, 35.9, 31.0, 26.6, 25.7, 21.4.
2-Cyclohexyl-7-(2,5-dimethylphenyl)-3-phenyl-1H-inden-1-one (3s). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3s as a yellow oil (53 mg, 68% yield). 1H NMR (600 MHz, CDCl3) δ 7.52 (t, J = 7.4 Hz, 2H), 7.48–7.44 (m, 1H), 7.42–7.38 (m, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 7.7, 1.2 Hz, 1H), 6.98–6.94 (m, 2H), 6.86 (dd, J = 7.3, 0.7 Hz, 1H), 2.42 (tt, J = 12.1, 3.4 Hz, 1H), 2.34 (s, 3H), 2.11 (s, 3H), 1.82–1.74 (m, 2H), 1.68 (s, 2H), 1.56 (s, 1H), 1.51 (d, J = 11.5 Hz, 2H), 1.18–1.09 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.3, 153.7, 146.2, 139.2, 139.0, 137.8, 134.7, 133.2, 132.6, 132.4, 131.0, 129.5, 129.3, 128.7, 128.6, 128.6, 128.0, 127.0, 119.4, 35.9, 30.9, 30.9, 26.5, 25.7, 21.0, 19.5. HRMS (ESI) calcd for C29H28NaO [M + Na]+ 415.2038, found 415.2025.
2-Cyclohexyl-7-(4-methoxyphenyl)-5-methyl-3-phenyl-1H-inden-1-one (3t). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3t as a yellow solid (61 mg, 75% yield), m.p.: 118.3–119.7 °C. 1H NMR (600 MHz, CDCl3) δ 7.52 (dd, J = 10.2, 4.6 Hz, 2H), 7.50–7.45 (m, 3H), 7.39–7.36 (m, 2H), 6.98 (dd, 2H), 6.89 (s, 1H), 6.61 (s, 1H), 3.86 (s, 3H), 2.42 (tt, J = 12.1, 3.3 Hz, 1H), 2.29 (s, 3H), 1.83–1.76 (m, 2H), 1.69 (d, J = 12.5 Hz, 2H), 1.56–1.52 (m, 2H), 1.24–1.07 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 197.0, 159.6, 153.1, 147.6, 143.4, 139.9, 139.6, 133.4, 130.9, 130.3, 129.8, 128.6, 128.6, 128.1, 123.4, 120.6, 113.3, 55.2, 36.0, 31.0, 26.6, 25.7, 21.8. HRMS (ESI) calcd for C29H28NaO2 [M + Na]+ 431.1987, found 431.1976.
2-Cyclohexyl-5-fluoro-7-(4-methoxyphenyl)-3-phenyl-1H-inden-1-one (3u). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3u as a yellow solid (58 mg, 70% yield), m.p.: 119.0–120.1 °C. 1H NMR (600 MHz, CDCl3) δ 7.53 (t, J = 7.4 Hz, 2H), 7.50–7.44 (m, 3H), 7.36 (dd, J = 5.1, 3.2 Hz, 2H), 7.01–6.96 (m, 2H), 6.75 (dd, J = 10.0, 2.2 Hz, 1H), 6.53 (dd, J = 8.1, 2.2 Hz, 1H), 3.86 (s, 3H), 2.45 (tt, J = 12.1, 3.4 Hz, 1H), 1.84–1.75 (m, 2H), 1.70 (d, J = 12.3 Hz, 2H), 1.59 (d, J = 10.1 Hz, 1H), 1.54 (s, 2H), 1.19–1.10 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 195.6, 165.5 (d, J = 254.3 Hz), 160.0, 151.6, 150.7 (d, J = 9.4 Hz), 142.3, 142.2, 140.7, 132.6, 130.3, 128.9, 128.8, 128.6, 128.0, 121.7, 115.7 (d, J = 22.5 Hz), 113.4, 108.1 (d, J = 25.3 Hz), 55.3, 36.1, 31.0, 26.5, 25.7. HRMS (ESI) calcd for C28H25FNaO2 [M + Na]+ 435.1736, found 435.1736.
5-Chloro-2-cyclohexyl-7-(4-methoxyphenyl)-3-phenyl-1H-inden-1-one (3v). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford 3v as a yellow solid (53 mg, 62% yield), m.p.: 93.5–94.3 °C. 1H NMR (600 MHz, CDCl3) δ 7.54 (dd, J = 10.2, 4.6 Hz, 2H), 7.49–7.46 (m, 3H), 7.36 (dd, J = 5.2, 3.2 Hz, 2H), 7.10 (d, J = 1.7 Hz, 1H), 7.00–6.96 (m, 2H), 6.77 (d, J = 1.7 Hz, 1H), 3.87 (s, 3H), 2.44 (tt, J = 12.1, 3.4 Hz, 1H), 1.83–1.75 (m, 2H), 1.70 (d, J = 12.2 Hz, 2H), 1.54 (d, J = 13.4 Hz, 2H), 1.23–1.09 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 195.9, 160.0, 152.5, 149.2, 141.1, 140.5, 138.6, 132.6, 130.4, 130.0, 129.0, 128.8, 128.4, 128.0, 123.9, 119.8, 113.4, 55.3, 36.1, 30.9, 26.5, 25.7. HRMS (ESI) calcd for C28H25ClNaO2 [M + Na]+ 451.1441, found 451.1426.
2-Cyclohexyl-4-methoxy-7-(4-methoxyphenyl)-3-phenyl-1H-inden-1-one (3w). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 50:1) to afford 3w as a yellow oil (62 mg, 73% yield). 1H NMR (600 MHz, CDCl3) δ 7.44–7.40 (m, 4H), 7.39–7.35 (m, 1H), 7.32–7.29 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.98–6.95 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 2.25 (tt, J = 12.2, 3.5 Hz, 1H), 1.76–1.72 (m, 2H), 1.64 (d, J = 12.9 Hz, 2H), 1.53 (s, 1H), 1.49–1.45 (m, 2H), 1.15–1.03 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 197.3, 159.3, 154.6, 152.3, 138.7, 135.8, 133.4, 133.0, 131.4, 130.3, 129.7, 129.4, 128.2, 127.8, 127.7, 127.5, 127.2, 119.5, 113.3, 55.9, 55.2, 35.7, 30.9, 26.5, 25.7. HRMS (ESI) calcd for C29H28NaO3 [M + Na]+ 447.1936, found 447.1960.
2-Isopropyl-7-(4-methoxyphenyl)-3-phenyl-1H-inden-1-one (3x). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 50:1) to afford 3x as a yellow solid (42 mg, 59% yield), m.p.: 90.8–91.7 °C. 1H NMR (600 MHz, CDCl3) δ 7.51 (t, J = 8.2 Hz, 4H), 7.45 (t, J = 7.4 Hz, 1H), 7.41–7.37 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 6.6 Hz, 1H), 3.87 (s, 3H), 2.81 (dt, J = 13.9, 7.0 Hz, 1H), 1.20 (d, J = 7.0 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 197.2, 159.7, 153.2, 147.0, 139.9, 139.8, 133.1, 132.6, 131.0, 130.4, 129.6, 128.7, 128.6, 128.0, 125.8, 119.3, 113.3, 55.2, 25.5, 21.4. HRMS (ESI) calcd for C25H22NaO2 [M + Na]+ 377.1517, found 377.1505.
2-(Pentan-2-yl)-3,7-diphenyl-1H-inden-1-one (3y). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 50:1) to afford 3y as a yellow oil (50 mg, 71% yield). 1H NMR (600 MHz, CDCl3) δ 7.48–7.41 (m, 4H), 7.39–7.36 (m, 2H), 7.34–7.29 (m, 3H), 7.19 (dd, J = 17.2, 9.7 Hz, 2H), 7.07–7.02 (m, 1H), 6.76 (dd, J = 7.2, 0.5 Hz, 1H), 2.59–2.53 (m, 1H), 1.68–1.58 (m, 1H), 1.38–1.32 (m, 1H), 1.13–1.08 (m, 5H), 0.67 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 197.1, 154.3, 147.0, 140.1, 139.0, 137.4, 133.1, 132.7, 131.0, 129.1, 128.7, 128.7, 128.1, 128.0, 127.9, 126.0, 119.5, 37.2, 30.6, 21.3, 19.8, 13.9.
2-(Pentan-3-yl)-3,7-diphenyl-1H-inden-1-one (3z). The product purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 50:1) to afford 3z as a yellow oil (46 mg, 65% yield). 1H NMR (600 MHz, CDCl3) δ 7.48–7.45 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.1 Hz, 3H), 7.33 (d, J = 7.3 Hz, 1H), 7.31–7.28 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.07–7.02 (m, 1H), 6.72 (d, J = 7.2 Hz, 1H), 2.27–2.20 (m, 1H), 1.69–1.59 (m, 2H), 1.48–1.42 (m, 2H), 0.72 (t, J = 7.5 Hz, 6H). 13C NMR (151 MHz, CDCl3) 197.2, 156.3, 147.2, 140.1, 137.3, 137.2, 133.2, 132.7, 131.1, 129.1, 128.6, 128.6, 128.1, 128.0, 127.9, 125.9, 119.5, 40.2, 26.6, 12.8.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29020458/s1. The supporting information include general considerations, radical trapping experiment, characterization data of products, and 1H NMR and 13C NMR spectra of the products.

Author Contributions

Conceptualization, W.W. and L.Y.; Funding acquisition, W.W.; Methodology, W.W. and L.Y.; Supervision, W.W.; Visualization, W.W. and L.Y.; Writing–original draft, W.W. and L.Y.; Writing—review and editing, W.W. All authors have read and agreed to the published version of the manuscript.

Funding

The study was jointly supported by the National Natural Science Foundation of China (32102302) and the Science and Technology Support Program (Agriculture) of Taizhou (TN202222).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We are especially grateful for Y. Yu, G. Fang, X. Yang and W. Xu for the assistance in project design, writing support, and providing instrumental guidance.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ahn, J.H.; Shin, M.S.; Jung, S.H.; Kim, J.A.; Kim, H.M.; Kim, S.H.; Kang, S.K.; Kim, K.R.; Rhee, S.D.; Park, S.D.; et al. Synthesis and structure–activity relationship of novel indene N-oxide derivatives as potent peroxisome proliferator activated receptor γ (PPARγ) agonists. Bioorg. Med. Chem. Lett. 2007, 17, 5239–5244. [Google Scholar] [CrossRef] [PubMed]
  2. Vasilyev, A.V.; Walspurger, S.; Pale, P.; Sommer, J. A new, fast and efficient synthesis of 3-aryl indenones: Intramolecular cyclization of 1, 3-diarylpropynones in superacids. Tetrahedron Lett. 2004, 45, 3379–3381. [Google Scholar] [CrossRef]
  3. Morrell, A.; Placzek, M.; Parmley, S.; Grella, B.; Antony, S.; Pommier, Y.; Cushman, M. Optimization of the indenone ring of indenoisoquinoline topoisomerase I inhibitors. J. Med. Chem. 2007, 50, 4388–4404. [Google Scholar] [CrossRef]
  4. Zhang, Y.; Sun, K.; Lv, Q.; Chen, X.; Qu, L.; Yu, B. Recent applications of radical cascade reaction in the synthesis of functionalized 1-indenones. Chin. Chem. Lett. 2019, 30, 1361–1368. [Google Scholar] [CrossRef]
  5. Larock, R.C.; Tian, Q.; Pletnev, A. Carbocycle synthesis via carbopalladation of nitriles. J. Am. Chem. Soc. 1999, 121, 3238–3239. [Google Scholar] [CrossRef]
  6. Jiang, B.; Huang, M.; Hao, W.; Li, G.; Tu, S. Recent advances in radical transformations of internal alkynes. Chem. Commun. 2018, 54, 10791–10811. [Google Scholar]
  7. Yang, W.C.; Zhang, M.M.; Feng, J.G. Recent advances in the construction of spiro compounds via radical dearomatization. Adv. Synth. Catal. 2020, 362, 4446–4461. [Google Scholar] [CrossRef]
  8. Xu, G.-Q.; Xu, P.-F. Visible light organic photoredox catalytic cascade reactions. Chem. Commun. 2021, 57, 12914–12935. [Google Scholar] [CrossRef]
  9. Fuentes, N.; Kong, W.; Fernández-Sánchez, L.; Merino, E.; Nevado, C. Cyclization Cascades via N-Amidyl Radicals toward Highly Functionalized Heterocyclic Scaffolds. J. Am. Chem. Soc. 2015, 137, 964–973. [Google Scholar] [CrossRef]
  10. Tang, B.; Liu, Y.; Lian, Y.; Liu, H. Radical Annulation using a Radical Reagent as a Two-Carbon Unit. Org. Biomol. Chem. 2022, 20, 9272–9281. [Google Scholar] [CrossRef]
  11. Sun, K.; Wang, X.; Li, C.; Wang, H.; Li, L. Recent advances in tandem selenocyclization and tellurocyclization with alkenes and alkynes. Org. Chem. Front. 2020, 7, 3100–3119. [Google Scholar] [CrossRef]
  12. Jiang, L.-L.; Qiu, H.; Zhou, Y.; Wang, L.-T.; Yang, W.-H.; Deng, C.; Wei, W.-T. Copper-catalyzed 1,2,2-trifunctionalization of maleimides with 1,7-enynes and oxime esters via radical relay/1,5-hydrogen-atom transfer. Org. Chem. Front. 2023, 10, 6096–6102. [Google Scholar] [CrossRef]
  13. Yang, W.; Chen, C.; Li, J.; Wang, Z. Radical denitrogenative transformations of polynitrogen heterocycles: Building C–N bonds and beyond. Chin. J. Catal. 2021, 42, 1865–1875. [Google Scholar] [CrossRef]
  14. 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]
  15. Zhang, M.-M.; Sun, Y.; Wang, W.-W.; Chen, K.-K.; Yang, W.-C.; Wang, L. Electrochemical synthesis of sulfonated benzothiophenes using 2-alkynylthioanisoles and sodium sulfinates. Org. Biomol. Chem. 2021, 19, 3844–3849. [Google Scholar] [CrossRef] [PubMed]
  16. Sun, K.; Chen, X.-L.; Zhang, Y.-L.; Li, K.; Huang, X.-Q.; Peng, Y.-Y.; Qu, L.-B.; Yu, B. Metal-free sulfonyl radical-initiated cascade cyclization to access sulfonated indolo[1,2-a]quinolines. Chem. Commun. 2019, 55, 12615–12618. [Google Scholar] [CrossRef] [PubMed]
  17. Sun, Y.; Zhang, S.-P.; Yang, W.-C. Divergent Construction of Thiochromanes and N-Arylbutanamides via Arylthiodifluoromethyl Radical-Triggered Cascade of Alkenes. J. Org. Chem. 2023, 88, 13279–13290. [Google Scholar] [CrossRef]
  18. Chen, Z.; Zhang, H.; Zhou, S.-F.; Cui, X. Metal-Free Sulfonylative Spirocyclization of Indolyl-ynones via Insertion of Sulfur Dioxide: Access to Sulfonated Spiro[cyclopentenone-1,3′-indoles]. Org. Lett. 2021, 23, 7992–7995. [Google Scholar] [CrossRef]
  19. Yuan, X.Y.; Zeng, F.L.; Zhu, H.L.; Liu, Y.; Lv, Q.Y.; Chen, X.L.; Peng, L.; Yu, B. A Metal-Free Visible-Light-Promoted Phosphorylation/Cyclization Reaction in Water towards 3-Phosphorylated Benzothiophenes. Org. Chem. Front. 2020, 7, 1884–1889. [Google Scholar] [CrossRef]
  20. Manna, S.; Prabhu, K.R. Visible-Light-Mediated Vicinal Difunctionalization of Activated Alkynes with Boronic Acids: Substrate-Controlled Rapid Access to 3-Alkylated Coumarins and Unsaturated Spirocycles. Org. Lett. 2023, 25, 810–815. [Google Scholar] [CrossRef]
  21. Song, H.-Y.; Xiao, F.; Jiang, J.; Wu, C.; Ji, H.-T.; Lu, Y.-H.; Wang, K.-L.; He, W.-M. External photocatalyst-free C-H alkylation of N-sulfonyl ketimines with alkanes under visible light. Chin. Chem. Lett. 2023, 34, 108509. [Google Scholar] [CrossRef]
  22. Yang, D.; Yan, Q.; Zhu, E.; Lv, J.; He, W.-M. Carbon–sulfur bond formation via photochemical strategies: An efficient method for the synthesis of sulfur-containing compounds. Chin. Chem. Lett. 2022, 33, 1798–1816. [Google Scholar] [CrossRef]
  23. Yang, W.; Sun, Y.; Bao, X.; Zhang, S.; Shen, L. A general electron donor–acceptor complex enabled cascade cyclization of alkynes to access sulfur-containing heterocycle. Green Chem. 2023, 25, 3111–3116. [Google Scholar] [CrossRef]
  24. Wang, Z.; Sun, Y.; Shen, L.-Y.; Yang, W.-C.; Meng, F.; Li, P. Photochemical and electrochemical strategies in C–F bond activation and functionalization. Org. Chem. Front. 2022, 9, 853–873. [Google Scholar] [CrossRef]
  25. Yang, W.; Yang, S.; Li, P.; Wang, L. Visible-light initiated oxidative cyclization of phenyl propiolates with sulfinic acids to coumarin derivatives under metal-free conditions. Chem. Commun. 2015, 51, 7520–7523. [Google Scholar] [CrossRef]
  26. Yang, W.-C.; Shen, L.-Y.; Li, J.N.; Feng, J.-G.; Li, P. Oxidative Cyclization of Aryl Ynones with NaNO2 for the Divergent Synthesis of NO2-Containing Spiro[5.5]trienones, Indenones and Thioflavones. Adv. Synth. Catal. 2022, 364, 3651–3656. [Google Scholar] [CrossRef]
  27. Zhang, Y.; Ma, C.; Struwe, J.; Feng, J.; Zhu, G.; Ackermann, L. Electrooxidative Dearomatization of Biaryls: Synthesis of Tri- and Difluoromethylated Spiro[5.5] trienones. Chem. Sci. 2021, 12, 10092–10096. [Google Scholar] [CrossRef]
  28. Yang, W.-C.; Zhang, M.-M.; Sun, Y.; Chen, C.-Y.; Wang, L. Electrochemical Trifluoromethylthiolation and Spirocyclization of Alkynes with AgSCF3: Access to SCF3-Containing Spiro[5,5] trienones. Org. Lett. 2021, 23, 6691–6696. [Google Scholar] [CrossRef]
  29. Xia, D.; Duan, X.-F. Alkylative Dearomatization by Using an Unactivated Aryl Nitro Group as a Leaving Group: Access to Diversified Alkylated Spiro[5.5]trienones. Org. Lett. 2021, 23, 2548–2552. [Google Scholar] [CrossRef]
  30. Zhang, Y.; Zhang, J.; Hu, B.; Ji, M.; Ye, S.; Zhu, G. Synthesis of Difluoromethylated and Phosphorated Spiro[5.5]-trienones via Dearomative Spirocyclization of Biaryl Ynones. Org. Lett. 2018, 20, 2988–2992. [Google Scholar] [CrossRef]
  31. Chen, S.; Yan, Q.; Fan, J.; Guo, C.; Li, L.; Liu, Z.Q.; Li, Z. Photo-induced spirocyclization of biaryl ynones with ammonium thiocyanate: Access to thiocyanate-featured spiro[5,5]trienones. Green Chem. 2023, 25, 153–160. [Google Scholar] [CrossRef]
  32. Yang, W.-C.; Sun, Y.; Shen, L.-Y.; Xie, X.; Yu, B. Photoinduced cyclization of aryl ynones with 4-alkyl-DHPs for the divergent synthesis of indenones, thioflavones and spiro[5.5] trienones. Mol. Catal. 2023, 535, 112819. [Google Scholar] [CrossRef]
  33. Zhang, M.M.; Shen, L.Y.; Dong, S.; Li, B.; Meng, F.; Si, W.J.; Yang, W.C. DTBP-Mediated Cascade Spirocyclization and Dearomatization of Biaryl Ynones: Facile Access to Spiro[5.5] trienones through C (sp3)−H Bond Functionalization. Eur. J. Org. Chem. 2021, 2021, 4465–4468. [Google Scholar] [CrossRef]
  34. Li, J.N.; Li, Z.J.; Shen, L.Y.; Li, P.; Zhang, Y.; Yang, W.C. Synthesis of polychloromethylated and halogenated spiro[5,5]trienones via dearomative spirocyclization of biaryl ynones. Org. Biomol. Chem. 2022, 20, 6659–6666. [Google Scholar] [CrossRef] [PubMed]
  35. Chen, F.; Zheng, Y.; Yang, H.; Yang, Q.Y.; Wu, L.Y.; Zhou, N. Iron-Catalyzed Silylation and Spirocyclization of Biaryl-Ynones: A Radical Cascade Process toward Silylated Spiro[5.5]trienones. Adv. Synth. Catal. 2022, 364, 1537–1542. [Google Scholar] [CrossRef]
  36. Xia, D.; Shen, L.Y.; Zhang, Y.; Yang, W.C. Radical spirocyclization of biaryl ynones for the construction of NO2-containing spiro[5.5]trienones. New J. Chem. 2022, 46, 20061–20064. [Google Scholar] [CrossRef]
  37. Chen, Z.; Zheng, X.; Zhou, S.F.; Cui, X. Visible light-induced selenylative spirocyclization of biaryl ynones toward the formation of selenated spiro[5.5]trienones. Org. Biomol. Chem. 2022, 20, 5779–5783. [Google Scholar] [CrossRef]
  38. Li, Y.; Li, L.; Guo, C.; Yan, Q.; Zhou, H.; Wang, Y.; Liu, Z.-Q.; Li, Z. Nitro-Spirocyclization of Biaryl Ynones with tert-Butyl Nitrite: Access to NO2-Substituted Spiro[5.5]trienones. J. Org. Chem. 2023, 88, 4854–4862. [Google Scholar] [CrossRef]
  39. Raji Reddy, C.; Kolgave, D.H.; Ajaykumar, U.; Ramesh, R. Copper(II)-catalyzed oxidative ipsoannulation of N-arylpropiolamides and biaryl ynones with 1,3-diketones: Construction of diketoalkyl spiro-trienones. Org. Biomol. Chem. 2022, 20, 6879–6889. [Google Scholar] [CrossRef]
  40. Reddy, C.R.; Ajaykumar, U.; Patil, A.D.; Ramesh, R. ipso-Cyclization of unactivated biaryl ynones leading to thio-functionalized spirocyclic enones. Org. Biomol. Chem. 2023, 21, 6379–6388. [Google Scholar] [CrossRef]
  41. Samanta, S.; Sarkar, D. Photoredox-Catalyzed Thiocyanative Cyclization of Biaryl Ynones to Thiocyanated Spiro[5.5]trienones: An External-Oxidant- and Transition-Metal-Free Approach. ChemPhotoChem. 2023, 7, e202200335. [Google Scholar] [CrossRef]
  42. Goulart, H.A.; Bartz, R.H.; Peglow, T.J.; Barcellos, A.M.; Cervo, R.; Cargnelutti, R.; Jacob, R.G.; Lenardão, E.J.; Perin, G. Synthesis of Seleno-Dibenzocycloheptenones/Spiro[5.5]Trienones by Radical Cyclization of Biaryl Ynones. J. Org. Chem. 2022, 87, 4273–4283. [Google Scholar] [CrossRef] [PubMed]
  43. Xia, D.; Duan, X.-F. Tandem vinyl radical Minisci-type annulation on pyridines: One-pot expeditious access to azaindenones. Chem. Commun. 2021, 57, 13570–13573. [Google Scholar] [CrossRef] [PubMed]
  44. Liao, Y.; Ran, Y.; Liu, G.; Liu, P.; Liu, X. Transition-metal-Free Radical Relay Cyclization of Vinyl Azides with 1,4-Dihydropyridines Involving a 1,5-Hydrogen-Atom Transfer: Access to α-Tetralone Scaffolds. Org. Chem. Front. 2020, 7, 3638–3647. [Google Scholar] [CrossRef]
  45. Jing, Q.; Qiao, F.; Sun, J.; Wang, J.; Zhou, M. Persulfate promoted carbamoylation of N-arylacrylamides and N-arylcinnamamides with 4-carbamoyl-Hantzsch esters. Org. Biomol. Chem. 2023, 21, 7530–7534. [Google Scholar] [CrossRef]
  46. Liu, X.; Liu, R.; Dai, J.; Cheng, X.; Li, G. Application of Hantzsch ester and Meyer nitrile in radical alkynylation reactions. Org. Lett. 2018, 20, 6906–6909. [Google Scholar] [CrossRef]
Molecules 29 00458 sch001
Scheme 1. Previous radical cascade reactions of biaryl ynone (a–c) and our work (d). PMP: p-methoxyphenyl.
Scheme 1. Previous radical cascade reactions of biaryl ynone (a–c) and our work (d). PMP: p-methoxyphenyl.
Molecules 29 00458 sch001
Molecules 29 00458 sch002
Scheme 2. Substrate scope. All reactions were performed with 1 (0.20 mmol), R-DHP (2, 0.4 mmol), Na2S2O8 (2.0 equiv), CH3CN/H2O (3:1, 2 mL), 60 °C, 12 h. Yields are given for isolated products. a R’ = OMe; b R’ = H.
Scheme 2. Substrate scope. All reactions were performed with 1 (0.20 mmol), R-DHP (2, 0.4 mmol), Na2S2O8 (2.0 equiv), CH3CN/H2O (3:1, 2 mL), 60 °C, 12 h. Yields are given for isolated products. a R’ = OMe; b R’ = H.
Molecules 29 00458 sch002
Molecules 29 00458 sch003
Scheme 3. Substrate scope. All reactions were performed with 1 (0.20 mmol), R-DHP (2, 0.4 mmol), Na2S2O8 (2.0 equiv), CH3CN/H2O (3:1, 2 mL), 60 °C, 12 h. Yields are given for isolated products.
Scheme 3. Substrate scope. All reactions were performed with 1 (0.20 mmol), R-DHP (2, 0.4 mmol), Na2S2O8 (2.0 equiv), CH3CN/H2O (3:1, 2 mL), 60 °C, 12 h. Yields are given for isolated products.
Molecules 29 00458 sch003
Molecules 29 00458 sch004
Scheme 4. The proposed mechanism.
Scheme 4. The proposed mechanism.
Molecules 29 00458 sch004
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 29 00458 i001
EntryOxidantSolventYield (%) b
1Na2S2O8acetone39
2Na2S2O8MeCN67
3Na2S2O8AcOEt56
4Na2S2O8MeCN/H2O (3:1)78
5Na2S2O8MeCN/H2O (2:1)70
6Na2S2O8MeCN/H2O (4:1)55
7Na2S2O8AcOEt/H2O (3:1)61
8K2S2O8MeCN/H2O (3:1)65
9(NH4)2S2O8MeCN/H2O (3:1)48
10TBHPMeCN/H2O (3:1)22
11DTBPMeCN/H2O (3:1)27
12 cNa2S2O8MeCN/H2O (3:1)77
13 dNa2S2O8MeCN/H2O (3:1)51
14 eNa2S2O8MeCN/H2O (3:1)63
15-MeCN/H2O (3:1)n.d.
a Reaction conditions: (1a, 0.20 mmol), Cy-DHP (2a, 0.40 mmol), Na2S2O8 (2.0 equiv), CH3CN/H2O (3:1, 2 mL), 60 °C, 12 h. b Isolated yields. c At 80 °C. d At 40 °C. e For 24 h. n.d. = not detected. TBHP: tert-butyl hydroperoxide; DTBP: di-tert-butyl peroxide.
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Wang, W.; Yu, L. Synthesis of Indenones via Persulfate Promoted Radical Alkylation/Cyclization of Biaryl Ynones with 1,4-Dihydropyridines. Molecules 2024, 29, 458. https://doi.org/10.3390/molecules29020458

AMA Style

Wang W, Yu L. Synthesis of Indenones via Persulfate Promoted Radical Alkylation/Cyclization of Biaryl Ynones with 1,4-Dihydropyridines. Molecules. 2024; 29(2):458. https://doi.org/10.3390/molecules29020458

Chicago/Turabian Style

Wang, Wanwan, and Lei Yu. 2024. "Synthesis of Indenones via Persulfate Promoted Radical Alkylation/Cyclization of Biaryl Ynones with 1,4-Dihydropyridines" Molecules 29, no. 2: 458. https://doi.org/10.3390/molecules29020458

APA Style

Wang, W., & Yu, L. (2024). Synthesis of Indenones via Persulfate Promoted Radical Alkylation/Cyclization of Biaryl Ynones with 1,4-Dihydropyridines. Molecules, 29(2), 458. https://doi.org/10.3390/molecules29020458

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