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Article

Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams

by
Hanyang Zhang
1,†,
Wen Liu
1,†,
Jiale Hu
1,
Qian Zhang
1,2,
Zeguo Fang
1,2,* and
Dong Li
1,2,*
1
School of Materials and Chemical Engineering, Hubei University of Technology, Wuhan 430068, China
2
New Materials and Green Manufacturing Talent Introduction and Innovation Demonstration Base, Hubei University of Technology, Wuhan 430068, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Catalysts 2024, 14(11), 797; https://doi.org/10.3390/catal14110797
Submission received: 12 October 2024 / Revised: 2 November 2024 / Accepted: 6 November 2024 / Published: 7 November 2024
(This article belongs to the Special Issue Recent Catalysts for Organic Synthesis)
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Abstract

:
An efficient method involving copper-catalyzed trifluoromethylthiolation and radical cyclization of N-phenylpent-4-enamides using readily available and stable AgSCF3 as the trifluoromethylthiolating reagent is described. The method enables the synthesis of a series of potential medicinally valuable trifluoromethylthio-substituted γ-lactams and relative 2-oxazolidinone derivatives with broad functional group compatibility. Mechanistic investigations indicated that this reaction involved amidyl radical-initiated cascade 5-exo-trig cyclization followed by trifluoromethylthiolation, resulting in the formation of new C-N and C-S bonds.

Graphical Abstract

1. Introduction

In recent years, the incorporation of fluorinated functional groups into organic molecules has gained significant attention, primarily due to the unique chemical and physical properties these groups impart to the molecules [1,2,3]. Among these, the trifluoromethylthio group (-SCF3) stands out for its exceptional electronegativity, lipophilicity, and metabolic stability, making it a valuable moiety in the fields of pharmaceuticals, agrochemicals, and materials science [4,5,6]. As a result, tremendous efforts have been devoted to the direct preparation of trifluoromethylthiolated compounds via electrophilic [7,8,9,10,11], nucleophilic [12,13,14,15,16], and radical [17,18,19,20,21] trifluoromethylthiolation. Recently, the SCF3• radical-cyclization pathway, initiated by stable and readily available silver trifluoromethylthiolate (AgSCF3) as the SCF3 radical source, has emerged as an efficient strategy for constructing SCF3-substituted compounds. In particular, Wang [22], Liang [23], Qing [24], and ourselves [25], along with others [26,27,28], have utilized this approach to synthesize SCF3-substituted cyclic compounds through trifluoromethylthiolation/cyclization of alkenes and alkynes. Despite these significant advances, there remains a strong demand for new methods to efficiently synthesize SCF3-containing compounds, particularly those with medicinally promising scaffolds.
γ-Lactams are a class of five-membered cyclic amides that are present in numerous bioactive natural products and pharmaceutical compounds. For instance, claudsenamide, an anti-dementia agent, and stemoamide, an antitussive agent, are notable γ-lactam derivatives that showcase their therapeutic potential in addressing critical health issues. Other representative examples of biologically active γ-lactam derivatives are illustrated in Scheme 1 [29]. Despite their significance in drug development, there is still a need to expand the variety of γ-lactam derivatives to synthesize those with specific biological activities. In the past few years, the cascade radical cyclization/functionalization of N-phenyl-4-pentenamides through amidyl radicals for the synthesis of γ-lactam derivatives has attracted great attention. For example, in 2013, Li reported an efficient silver-catalyzed radical fluorination/cyclization of various N-arylpent-4-enamides to afford 5-fluoromethyl-substituted γ-lactams [30]. Afterward, in 2018, Rueping disclosed the synthesis of alkyne and alkene-decorated γ-lactams through the photocatalytic proton-coupled electron transfer (PCET) activation of N-phenyl-4-pentenamides [31]. Later, Molander successively developed a photoredox PCET/Ni dual-catalyzed amidoarylation and aminoacylation of N-phenyl-4-pentenamides to construct γ-lactam derivatives [32,33]. More recently, Weng [34] and Pan [35] have described a mild photoredox catalytic approach to accessing sulfonyl fluoride and gem-difluoroalkene-substituted γ-lactams via radical cascade cyclization of N-phenyl-4-pentenamides, respectively (Scheme 2, top). Inspired by these elegant results and our ongoing interest in trifluoromethylthiolation [25] and γ-lactams [36,37,38,39], we became interested in preparing SCF3-substituted γ-lactams that may be useful in medicinal chemistry. Herein, we disclose a method involving copper-catalyzed trifluoromethylthiolation and radical cyclization of N-phenyl-4-pentenamides using stable and easily operable AgSCF3 to access SCF3-substituted γ-lactams (Scheme 2, bottom).

2. Results and Discussion

In our initial investigation, N-phenylpent-4-enamide 1a and AgSCF3 2 were selected as the model substrates to screen the reaction conditions, and the results are summarized in Table 1. To our delight, the desired trifluoromethylthiolated product 3a was obtained in 55% yield when the reaction was conducted with Cu(OAc)2 (0.2 mmol) and K2S2O8 (1.5 equiv.) in the H2O/DMSO (1/1, v/v) at 80 °C for 12 h (entry 1). Subsequent tests revealed that Cu(OAc)2 was essential in enhancing the reaction efficiency, as other copper salts, whether Cu(I) or Cu(II), led to inferior results (entries 2–8). This is likely due to Cu(OAc)2’s superior ability to generate amidyl radical intermediates, which is crucial for the desired radical cyclization process [40,41,42]. When water or DMSO was used as the sole solvent, the yield of 3a dropped to 0% or 43%, respectively (entries 9, 10). These results revealed that water and DMSO mixture solvent may be the best solvent system for the reaction. Further variation in the ratio of mixed solvent systems showed that a H2O/DMSO (1:3, v/v) mixture resulted in an improved yield of 67% (entries 11, 12). Next, different oxidants were tested in order to improve yield further, but K2S2O8 consistently gave the best results (entries 13–17), which is consistent with the literature indicating that S2O82− is effective for the formation of SCF3 radicals [22,23,24]. Finally, the effects of reaction temperature and time were investigated. The results indicated that increasing the reaction temperature to 100 °C further boosted the yield to 73% (entries 18 and 19). Additionally, shortening the reaction time to 6 h did not reduce the yield (entries 20 and 21; for more details regarding the screening of conditions, refer to the Supporting Information). Therefore, the conditions described in entry 20 were selected as the optimal conditions.
With the optimized conditions established, we then set out to investigate the cascade cyclization reaction between various N-arylpent-4-enamides 1 and AgSCF3, as summarized in Figure 1. Various substrates containing either an electron-donating (3b, 3c, 3f) or electron-withdrawing (3d, 3e) group at the para-position of the aryl group were all tolerated under reaction conditions, leading to the desired products in moderate to good yields. N-phenylpent-4-enamides with ortho- or meta-substitutions also reacted efficiently with 2, producing trifluoromethylthiolated γ-lactam products in 42–66% yields (3g–3k). Even when substrates had two substituents on the phenyl ring, including one at the meta-position (3p, 3q), the reaction efficiency was not significantly impacted, leading to the formation of products (3m–3r), which shows that the steric hindrance of N-phenylpent-4-enamide did not affect this transformation. Furthermore, substrates with the methyl group at the α-carbonyl position were tried and were compatible with this reaction as well (3s, 3t). Finally, to explore the scope of this transformation, several carbamate substrates were examined under the standard reaction condition and resulted in good yields (3u–3x).
To gain deeper insight into the plausible reaction mechanism, we performed several control experiments (Scheme 3, top). First, when 1a and 2 were subjected to the reaction conditions without Cu(OAc)2, the desired product 3 did not form. This indicates that copper plays a crucial role in the catalytic cycle. Furthermore, the addition of the radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) to the standard reaction of 1a and 2 resulted in the total inhibition of the reaction, suggesting the possible involvement of a radical process. Notably, the TEMPO-trapped product 4 was observed by 1H NMR spectroscopy in approximately 20% yield [38]. Despite the lack of complete clarity on the process of this transformation, a feasible reaction mechanism was postulated based on prior studies and the experimental data mentioned above (Scheme 3, bottom). Firstly, Cu(OAc)2 facilitated the formation of an amidyl radical via N-H bond activation [40,41,42]. Subsequently, the amidyl radical underwent addition to the C=C bond, resulting in the formation of intermediate B via 5-exo-trig cyclization. Meanwhile, AgSCF3 was oxidized by K2S2O8 to generate the AgII(SCF3)2, which further transformed into CF3SSCF3 [22,23,24]. Finally, CF3SSCF3 decomposed and released a SCF3 radical, which was coupled with B to give the trifluoromethylthiolation product 3a.

3. Experimental Section

General Information: 1H NMR (400 MHz), 13C NMR (100 MHz), and 19F NMR (376 MHz) spectra were recorded on a Bruker NMR apparatus (Bremen, Germany) with CDCl3 as the solvent. The chemical shifts are reported in δ (ppm) values. 1H NMR chemical shifts were determined relative to the internal tetramethylsilane signal at δ 0.0. 19F NMR chemical shifts were determined relative to external CHCl3 at δ 0.0. Data for 1H, 13C, and 19FNMR were recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets, br = broad). Coupling constants (J) are reported in Hertz (Hz). Melting points were measured by SGW X-4A microscopic apparatus (Shanghai INESA Physico-Optical Instrument Co., Ltd., Shanghai, China). HRMS was measured by Q Exactive Hybrid Quadrupole-Orbitrap LC/MS spectrometer (Thermo Fisher Scientific, Waltham, MA, USA). The starting materials, including the aniline, 4-pentene acid, phosphorus oxychloride, and triethylamine, were obtained from commercial sources such as Aladdin (Calhoun, GA, USA), Macklin (Shanghai, China), Alfa Aesar (Ward Hill, MA, USA), and Ourchem (Guangzhou, China) and used as received unless otherwise noted. Ethyl acetate (Titanchem, Shanghai, China) and petroleum ether (Titanchem, Shanghai, China) were used for column chromatography without further purification.
General procedure for the synthesis of desired products forming SCF3-substituted γ-lactams (3a–3x).
A mixture of substituted N-phenylpent-4-enamides (1, 0.2 mmol), AgSCF3 (2, 0.3 mmol), K2S2O8 (0.3 mmol), and Cu(OAc)2 (0.04 mmol) in H2O/DMSO (1:3, 2 mL) was stirred at 100 °C for 6 h. After the reaction was completed, it was quenched with saturated NaHCO3, and the crude solution was separated after diluting with ethyl acetate and dried over anhydrous Na2SO4. The solvent was removed in vacuum to obtain the crude product, which was further separated and purified by column chromatography to give the desired products (3a–3x).
1-phenyl-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3a): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.40–7.31 (m, 2H), 7.29 (d, J = 7.5 Hz, 2H), 7.22–7.15 (m, 1H), 4.51–4.38 (m, 1H, CH), 3.10 (dd, J = 13.8, 3.0 Hz, 1H), 2.80 (dd, J = 13.8, 8.3 Hz, 1H), 2.69–2.46 (m, 2H), 2.45–2.35 (m, 1H), 1.99–1.89 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.9, 135.5, 129.6 (q, J = 307.0 Hz), 128.4, 125.5, 122.9, 57.4, 32.0 (q, J = 2.0 Hz), 29.6, 22.0. 19F NMR (376 MHz, CDCl3) δ −40.65. HRMS: Cal. C12H12OF3NS (M + H)+: 276.0664, found 276.0665.
1-(4-methylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3b): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 4H), 4.52–4.42 (m, 1H, CH), 3.15 (dd, J = 13.7, 2.8 Hz, 1H), 2.87 (dd, J = 13.7, 8.3 Hz, 1H), 2.74–2.52 (m, 2H), 2.52–2.39 (m, 1H), 2.35 (s, 3H), 2.05–1.97 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.1, 136.7, 133.9, 132.2 (q, J = 304.4 Hz), 130.1, 124.2, 58.7, 33.2 (q, J = 1.9 Hz), 30.7, 23.1, 21.1. 19F NMR (376 MHz, CDCl3) δ −40.56. HRMS: Cal. C13H14OF3NS (M + H)+: 290.0821, found 290.0822.
1-(4-ethylphenyl)-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3c): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 4H), 4.53–4.42 (m, 1H, CH), 3.16 (dd, J = 13.7, 3.0 Hz, 1H), 2.92–2.83 (m, 1H), 2.74–2.54 (m, 4H), 2.51–2.39 (m, 1H), 2.07–1.97 (m, 1H), 1.23 (d, J = 7.6 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 174.1, 142.9, 134.0, 131.0 (q, J = 394.7 Hz), 128.9, 124.2, 58.7, 33.1 (q, J = 1.8 Hz), 30.7, 28.4, 23.0, 15.4. 19F NMR (376 MHz, CDCl3) δ −40.64. HRMS: C14H16OF3NS (M + H)+: 303.0905, found 303.0906.
1-(4-chlorophenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3d): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.55–4.45 (m, 1H, CH), 3.21–3.10 (m, 1H), 2.87 (dd, J = 13.8, 8.3 Hz, 1H), 2.75–2.64 (m, 1H), 2.63–2.53 (m, 1H), 2.53–2.41 (m, 1H), 2.08–1.96 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.0, 135.2, 131.9, 130.6 (q, J = 305.5 Hz), 129.6, 124.9, 58.3, 32.9 (q, J = 1.8 Hz), 30.6, 23.0. 19F NMR (376 MHz, CDCl3) δ −40.49. HRMS: C12H11OClF3NS (M + H)+: 310.0275, found 310.0276.
1-[4-(trifluoromethyl)phenyl]-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3e): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 4.73–4.62 (m, 1H, CH), 3.21 (dd, J = 14.0, 2.8 Hz, 1H), 2.94 (dd, J = 8.8, 8.4 Hz, 1H), 2.86–2.74 (m, 1H), 2.74–2.63 (m, 1H), 2.64–2.53 (m, 1H), 2.19–2.08 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 171.3, 139.9, 130.3 (q, J = 308.0 Hz), 127.9 (d, J = 35.8Hz), 126.5 (q, J = 3.8 Hz), 126.2 (d, J = 3.6 Hz), 123.8 (d, J = 273.9 Hz), 122.8, 118.4, 58.0, 32.7 (q, J = 1.8 Hz), 30.7, 22.8. 19F NMR (376 MHz, CDCl3) δ −40.52, −62.48. HRMS:Cal. C13H11OF6NS (M + H)+: 344.0538, found 344.0533.
1-(4-methoxyphenyl)-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3f): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 4.45–4.36 (m, 1H, CH), 3.81 (s, 3H, OCH3), 3.12 (dd, J = 13.7, 3.1 Hz, 1H), 2.94–2.82 (m, 1H), 2.71–2.56 (m, 2H), 2.51–2.38 (m, 1H), 2.06–1.93 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.2, 158.2, 130.7 (q, J = 306.7 Hz), 129.2, 126.1, 114.7, 59.0, 55.5, 33.2 (q, J = 1.9 Hz), 30.5, 23.1. 19F NMR (376 MHz, CDCl3) δ −40.72. HRMS: Cal. C13H14O2F3NS (M + H)+: 305.0697, found 305.0698.
1-(3-fluorophenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3g): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.31 (q, J = 8.1 Hz, 1H), 7.24–7.16 (m, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.94–6.84 (m, 1H), 4.55–4.38 (m, 1H, CH), 3.27–3.08 (m, 1H), 2.82 (dd, J = 13.9, 8.5 Hz, 1H), 2.71–2.58 (m, 1H), 2.59–2.46 (m, 1H), 2.46–2.34 (m, 1H), 2.03–1.90 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.8, 162.1 (d, J = 247.8 Hz), 137.2 (d, J = 10.3 Hz), 129.6 (q, J = 307.6 Hz), 129.5 (d, J = 9.7 Hz), 117.3 (d, J = 2.9 Hz), 112.2 (d, J = 21.5 Hz), 109.9 (d, J = 24.5 Hz), 57.2, 31.7 (q, J = 1.8 Hz), 29.6, 21.8. 19F NMR (376 MHz, CDCl3) δ −40.59, −110.64. HRMS: Cal. C12H11OF4NS (M + H)+: 294.0570, found 294.0572.
1-[3-(trifluoromethyl)phenyl]-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3h): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 4.69–4.48 (m, 1H, CH), 3.21 (d, J = 13.6 Hz, 1H), 2.99–2.81 (m, 1H), 2.79–2.69 (m, 1H), 2.69–2.58 (m, 1H), 2.56–2.43 (m, 1H), 2.16–2.01 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.1, 137.3, 130.6 (d, J = 223.1 Hz), 130.5 (q, J = 301.5Hz), 130.1, 127.7 (d, J = 34.9 Hz), 126.6, 122.9 (q, J = 3.7 Hz), 119.8 (d, J = 3.9 Hz), 58.2, 32.7 (q, J = 1.8 Hz), 30.6, 22.9. 19F NMR (376 MHz, CDCl3) δ −40.61, −62.79. HRMS: Cal. C13H11OF6NS (M + H)+: 344.0538, found 344.0535.
1-(3-chlorophenyl)-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3i): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.45 (t, J = 2.1 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.29–7.19 (m, 2H), 4.60–4.41 (m, 1H, CH), 3.18 (dd, J = 13.9, 2.9 Hz, 1H), 2.94–2.81 (m, 1H), 2.75–2.64 (m, 1H), 2.64–2.54 (m, 1H), 2.52–2.44 (m, 1H), 2.11–1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 173.9, 137.8, 135.1, 130.5 (q, J = 306.9 Hz), 130.4, 126.5, 123.7, 121.4, 58.3, 32.8 (q, J = 1.8 Hz), 30.6, 22.9. 19F NMR (376 MHz, CDCl3) δ −40.57. HRMS: Cal. C12H11ClF3NOS (M + H)+: 309.0202, found 309.0203.
1-(3-bromophenyl)-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3j): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.62 (t, J = 2.0 Hz, 1H), 7.40 (dt, J = 7.5, 1.7 Hz, 1H), 7.37–7.33 (m, 1H), 7.33–7.28 (m, 1H), 4.59–4.42 (m, 1H, CH), 3.20 (dd, J = 13.9, 2.9 Hz, 1H), 2.90 (dd, J = 13.9, 8.4 Hz, 1H), 2.78–2.66 (m, 1H), 2.66–2.55 (m, 1H), 2.54–2.42 (m, 1H), 2.12–1.98 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 173.9, 138.0, 130.6, 130.3 (q, J = 307.2 Hz), 129.4, 126.6, 122.9, 121.9, 58.3, 32.8 (q, J = 1.8 Hz), 30.6, 22.9. 19F NMR (376 MHz, CDCl3) δ −40.57. HRMS: Cal. C12H11OBrF3NS (M + H)+: 352.9697, found 302.9698.
1-(2-fluorophenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3k): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.37–7.27 (m, 2H), 7.24–7.13 (m, 2H), 4.49–4.32 (m, 1H, CH), 3.05 (dd, J = 13.7, 3.3 Hz, 1H), 2.88 (dd, J = 13.6, 7.7 Hz, 1H), 2.72–2.44 (m, 3H), 2.13–1.97 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.6, 157.7 (d, J = 252.0 Hz), 130.6 (q, J = 306.3 Hz), 129.6 (d, J = 8.1 Hz), 129.5 (d, J = 1.5 Hz), 124.9 (d, J = 3.7 Hz), 123.8 (d, J = 12.1 Hz), 116.9 (d, J = 19.9 Hz), 58.7 (d, J = 3.3 Hz), 33.3 (q, J = 1.7 Hz), 30.0, 23.9. 19F NMR (376 MHz, CDCl3) δ −40.90, −119.90–−119.96. HRMS: Cal. C12H11OF4NS (M + H)+: 294.0570, found 294.0573.
1-(2,5-dimethylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3l): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 19.1 Hz, 3H), 4.54–4.37 (m, 1H, CH), 3.15 (dd, J = 13.8, 2.7 Hz, 1H), 2.85 (dd, J = 13.7, 8.4 Hz, 1H), 2.68–2.52 (m, 2H), 2.50–2.40 (m, 1H), 2.32 (s, 6H, CH3), 2.06–1.93 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.0, 139.1, 136.3, 130.7 (q, J = 306.4 Hz), 128.6, 122.0, 121.2, 121.7, 58.8, 33.0 (q, J = 1.8Hz), 30.7, 29.7, 23.1, 21.3. 19F NMR (376 MHz, CDCl3) δ −40.65. HRMS: Cal. C14H16OF3NS (M + H)+: 304.0977, found 304.0975.
1-(3-fluoro-4-methylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3m): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.24–7.10 (m, 2H), 7.01 (dd, J = 8.2, 2.1 Hz, 1H), 4.50–4.44 (m, 1H, CH), 3.17 (dd, J = 13.8, 2.9 Hz, 1H), 2.88 (dd, J = 13.8, 8.4 Hz, 1H), 2.69–2.54 (m, 2H), 2.51–2.39 (m, 1H), 2.26 (s, 3H, CH3), 2.09- 1.96 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.8, 160.2 (d, J = 244.3Hz), 134.5(d, J = 9.9 Hz), 130.9(d, J = 6.3 Hz), 129.6 (q, J = 307.5 Hz), 122.1 (d, J = 17.3 Hz), 117.6 (d, J = 3.5 Hz), 109.9 (d, J = 25.6 Hz), 57.3, 31.8 (q, J = 1.8 Hz), 29.5, 21.8, 13.1 (d, J = 3.2 Hz). 19F NMR (376 MHz, CDCl3) δ −40.60, −114.43–−114.61. HRMS: Cal. C13H13OF4NS (M + H)+: 308.0727, found 308.0729.
1-(3-chloro-4-methylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3n): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.3 Hz, 1H), 7.29–7.23 (m, 1H), 7.15 (dd, J = 8.2, 2.2 Hz, 1H), 4.54–4.40 (m, 1H, CH), 3.15 (dd, J = 13.8, 2.9 Hz, 1H), 2.92–2.81 (m, 1H), 2.71–2.62 (m, 1H), 2.62–2.53 (m, 1H), 2.50–2.41 (m, 1H), 2.36 (s, 3H, CH3), 2.09–1.97 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.9 134.3, 133.9, 133.4, 130.4, 129.6 (q, J = 305.6Hz), 123.4, 120.9, 57.3, 31.8 (q, J = 1.6 Hz), 29.5, 21.9, 18.6. 19F NMR (376 MHz, CDCl3) δ −40.59. HRMS: Cal. C13H13OClF3NS (M + H)+: 324.0431, found 324.0432.
1-(3-bromo-4-methylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3o): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.14 (dd, J = 8.2, 2.1 Hz, 1H), 4.47–4.29 (m, 1H, CH), 3.09 (dd, J = 13.8, 2.9 Hz, 1H), 2.81 (dd, J = 13.8, 8.3 Hz, 1H), 2.68–2.47 (m, 2H), 2.44–2.35 (m, 1H), 2.30 (s, 3H, CH3), 1.99–1.89 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.9, 135.3, 134.3, 130.2, 129.3 (q, J = 305.1 Hz), 126.5, 124.1, 121.6, 57.3, 31.8 (d, J = 1.8 Hz), 29.5, 21.9, 21.5. 19F NMR (376 MHz, CDCl3) δ −40.58. HRMS: Cal. C13H13OBrF3NS (M + H)+: 367.9926, found 367.9925.
1-(2-fluoro-4-methylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3p): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.24–7.06 (m, 1H), 7.10–6.89 (m, 2H), 4.43–4.27 (m, 1H, CH), 3.05 (dd, J = 13.6, 3.5 Hz, 1H), 2.88 (dd, J = 13.6, 7.7 Hz, 1H), 2.68–2.56 (m, 2H), 2.53–2.44 (m, 1H), 2.36 (s, 3H, CH3), 2.08–1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 173.6, 156.5 (d, J = 250.9 Hz), 139.5 (d, J = 7.8 Hz), 130.1 (q, J = 306.3 Hz), 128.1 (d, J = 2.0 Hz), 124.6 (d, J = 3.2 Hz), 119.9 (d, J = 12.4 Hz), 116.3 (d, J = 19.6 Hz), 57.7 (d, J = 3.0 Hz), 32.3 (d, J = 1.6 Hz), 28.9, 22.8, 20.2 (d, J = 1.3 Hz), 19F NMR (376 MHz, CDCl3) δ −40.89, −121.00–−121.05. HRMS: Cal. C13H13OF4NS (M + H)+: 308.0727, found 308.0725.
1-(2,4-dimethylphenyl)-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3q): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1HNMR (400 MHz, CDCl3) δ 7.10 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 4.40–4.04 (m, 1H, CH), 3.04 (dd, J = 13.5, 3.6 Hz, 1H), 2.91–2.76 (m, 1H), 2.68–2.55 (m, 2H), 2.55–2.44 (m, 1H), 2.32 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.09–1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.3, 138.4, 135.9, 132.3, 130.6 (q, J = 306.3 Hz), 127.8, 33.3, 30.1, 24.2, 21.01, 18.0. 19F NMR (376 MHz, CDCl3) δ −40.92. HRMS: Cal. C14H16OF3NS (M + H)+: 303.0905, found 303.0906.
1-(3,5-dimethylphenyl)-5-{[(trifluoromethyl)sulfanyl]methyl}pyrrolidin-2-one (3r): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 6.95 (s, 2H), 6.90 (s, 1H), 4.50–4.41 (m, 1H, CH), 3.16 (dd, J = 13.7, 2.9 Hz, 1H), 2.85 (dd, J = 13.8, 8.4 Hz, 1H), 2.75–2.55 (m, 2H), 2.50–2.41 (m, 1H), 2.32 (s, 6H, CH3), 2.07–1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.0, 139.1, 136.3, 130.7 (q, J = 306.1 Hz), 128.5, 121.9, 58.8, 33.1 (q, J = 1.8 Hz), 30.7, 23.1, 21.4. 19F NMR (376 MHz, CDCl3) δ −40.65. HRMS: Cal. C14H16OF3NS (M + H)+: 303.0905, found 303.0902.
3-methyl-1-phenyl-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3s): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.47–7.37 (m, 4H), 7.25–7.20 (m, 1H), 4.52–4.41 (m, 1H, CH), 3.16 (dd, J = 13.9, 3.0 Hz, 1H), 2.91–2.71 (m, 2H), 2.36–2.26 (m, 1H), 2.10–2.00 (m, 1H), 1.29 (dd, J = 7.2 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 176.3, 136.9, 132.2 (q, J = 307.1 Hz), 129.4, 126.1, 123.0, 56.6, 36.0, 32.3 (q, J = 1.7 Hz), 31.5, 16.3. 19F NMR (376 MHz, CDCl3) δ −40.63. HRMS: Cal. C13H14OF3NS (M + H)+: 289.0748, found 289.0749.
3,3-dimethyl-1-phenyl-5-(((trifluoromethyl)thio)methyl)pyrrolidin-2-one (3t): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.45–7.38 (m, 2H), 7.33–7.29 (m, 2H), 7.28–7.22 (m, 1H), 4.47–4.33 (m, 1H, CH), 3.22 (dd, J = 13.7, 3.1 Hz, 1H), 2.81 (ddd, J = 13.7, 8.7, 0.9 Hz, 1H), 2.34 (dd, J = 13.0, 7.2 Hz, 1H), 1.81 (dd, J = 13.0, 7.7 Hz, 1H), 1.33 (s, 3H, CH3), 1.24 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 179.0, 136.7, 130.7 (q, J = 307.2 Hz), 129.3, 126.5, 124.2, 54.8, 40.8, 39.4, 33.5 (q, J = 1.8 Hz), 25.7, 25.3. 19F NMR (376 MHz, CDCl3) δ −40.69. HRMS: Cal. C14H16OF3NS (M + H)+: 303.0905, found 303.0906.
3-(4-fluorophenyl)-4-(((trifluoromethyl)thio)methyl)oxazolidin-2-one (3u): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 9.4 Hz, 2H), 4.81–4.72 (m, 1H), 4.69–4.62 (m, 1H, CH), 4.37 (dd, J = 9.3, 3.8 Hz, 1H), 3.37–3.28 (m, 1H), 3.01–2.91 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 153.3, 138.0 (d, J = 1.1 Hz), 129.3 (q, J = 308.4 Hz), 126.3 (d, J = 32.8 Hz), 125.3 (d, J = 3.8 Hz), 125.8 (d, J = 11.4 Hz), 122.8 (d, J = 270.7 Hz), 119.0, 64.7, 54.0, 29.9 (q, J = 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ −40.16, −62.41. HRMS: Cal. C11H9O2F3NS (M + H)+: 295.0290, found 295.0291.
2-(4-chlorophenyl)-4-(((trifluoromethyl)thio)methyl)oxazolidin-2-one (3v): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 4H), 4.71–4.65 (m, 1H, CH), 4.65–4.60 (m, 1H), 4.32 (dd, 1H), 3.27 (ddd, J = 14.5, 2.8, 1.0 Hz, 1H), 3.03–2.87 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 153.7, 133.3, 130.3, 129.3 (q, J = 307.9 Hz), 128.7, 121.5, 64.7, 54.4, 30.0 (q, J = 1.8 Hz). 19F NMR (376 MHz, CDCl3) δ −40.27. HRMS: Cal. C11H9O2ClF3NS (M + H)+: 210.9995, found 310.9996.
3-(4-bromophenyl)-4-(((trifluoromethyl)thio)methyl)oxazolidin-2-one (3w): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.57–7.51 (m, 2H), 7.38–7.29 (m, 2H), 4.73–4.65 (m, 1H, CH), 4.65–4.60 (m, 1H), 4.35–4.28 (m, 1H), 3.35–3.21 (m, 1H), 2.95 (dd, 1H). 13C NMR (101 MHz, CDCl3) δ 153.6, 133.8, 131.7, 129.1 (q, J = 306.3 Hz), 121.7, 118.0, 64.7, 54.3, 30.0 (q, J = 1.8 Hz). 19F NMR (376 MHz, CDCl3) δ −40.25. HRMS: Cal. C11H9O2BrF3NS (M + H)+: 354.9489, found 354.9490.
3-(4-(trifluoromethyl)phenyl)-4-(((trifluoromethyl)thio)methyl)oxazolidin-2-one (3x): The target product was synthesized as a colorless oil and purified by column chromatography (ethyl acetate/petroleum ether = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 4.82–4.71 (m, 1H, CH), 4.65 (t, J = 8.7 Hz, 1H), 4.36 (dd, J = 9.3, 3.8 Hz, 1H), 3.33 (dd, J = 14.7, 2.8 Hz, 1H), 2.97 (dd, J = 14.6, 9.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 154.4, 139.0 (d, J = 1.3 Hz), 130.3 (d, J = 306.1 Hz), 127.3 (d, J = 33.2 Hz), 126.8 (d, J = 11.4 Hz), 126.8 (q, J = 3.8 Hz), 123.7 (d, J = 271.8 Hz), 120.1, 65.7, 55.1, 30.9 (d, J = 1.8 Hz). 19F NMR (376 MHz, CDCl3) δ −40.17, −62.42. HRMS: Cal. C12H9O2F6NS (M + H)+: 345.0258, found 345.0259.

4. Conclusions

In summary, we have developed an efficient method for copper-catalyzed trifluoromethylthiolation and cyclization reaction of N-phenylpent-4-enamides using the stable and operationally simple AgSCF3 as the trifluoromethylthiolation reagent. This methodology allows for the synthesis of novel and potentially valuable SCF3-containing γ-lactam derivatives, which are characterized by a broad substrate scope and excellent functional group compatibility. Mechanistic studies indicate that the reaction likely proceeds via a radical pathway, facilitating the formation of new C-N and C-S bonds. We believe that these γ-lactam derivatives have important application value in the development of new drugs in the future.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal14110797/s1.

Author Contributions

Formal analysis, H.Z.; investigation, H.Z., W.L. and J.H.; writing—original draft preparation, Z.F.; writing—review and editing, D.L.; supervision, Q.Z., Z.F. and D.L.; project administration, D.L. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to the Scientific Research Project of the Department of Education of Hubei Province (T2020023), the Department of Science and Technology of Hubei Province (2022BAD056), and the Hubei University of Technology (XJKY20220023) for financial support.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author(s).

Acknowledgments

We thank Nawaf Al-Maharik (An Najah National University) for his kind assistance during the course of this study.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 14 00797 sch001
Scheme 1. Representative examples of bioactive γ-lactam derivatives.
Scheme 1. Representative examples of bioactive γ-lactam derivatives.
Catalysts 14 00797 sch001
Catalysts 14 00797 sch002
Scheme 2. Strategies to construct trifluoromethylthiolated γ-lactams [30,31,32,33,34,35].
Scheme 2. Strategies to construct trifluoromethylthiolated γ-lactams [30,31,32,33,34,35].
Catalysts 14 00797 sch002
Catalysts 14 00797 g001
Figure 1. Substrate scope of N-arylpent-4-enamides (1). Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), Cu(OAc)2 (0.2 equiv.), oxidant (1.5 equiv.) in DMSO/H2O (3:1, 2.0 mL) at 100 °C for 6 h; isolated yield.
Figure 1. Substrate scope of N-arylpent-4-enamides (1). Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), Cu(OAc)2 (0.2 equiv.), oxidant (1.5 equiv.) in DMSO/H2O (3:1, 2.0 mL) at 100 °C for 6 h; isolated yield.
Catalysts 14 00797 g001
Catalysts 14 00797 sch003
Scheme 3. Control experiments and plausible mechanism.
Scheme 3. Control experiments and plausible mechanism.
Catalysts 14 00797 sch003
Table 1. Optimization of the reaction conditions a,b.
Table 1. Optimization of the reaction conditions a,b.
Catalysts 14 00797 i001
Entry[Cu]OxidantSolventT (°C)t (h)Yield (%) b
1Cu(OAc)2K2S2O8H2O/DMSO (1:1)801255
2CuSO4K2S2O8H2O/DMSO (1:1)801247
3CuCl2K2S2O8H2O/DMSO (1:1)801246
4Cu(acac)2K2S2O8H2O/DMSO (1:1)801226
5CuBr2K2S2O8H2O/DMSO (1:1)801245
6CuOK2S2O8H2O/DMSO (1:1)80127
7Cu2OK2S2O8H2O/DMSO (1:1)801238
8CuClK2S2O8H2O/DMSO (1:1)801232
9Cu(OAc)2K2S2O8H2O8012NR
10Cu(OAc)2K2S2O8DMSO801243
11Cu(OAc)2K2S2O8H2O/DMSO (1:2)801262
12Cu(OAc)2K2S2O8H2O/DMSO (1:3)801267
13Cu(OAc)2Na2S2O8H2O/DMSO (1:3)801226
14Cu(OAc)2(NH4)2S2O8H2O/DMSO (1:3)801264
15Cu(OAc)2TBHPH2O/DMSO (1:3)8012NR
16Cu(OAc)2m-CPBAH2O/DMSO (1:3)8012NR
17Cu(OAc)2DTBPH2O/DMSO (1:3)8012NR
18Cu(OAc)2K2S2O8H2O/DMSO (1:3)601253
19Cu(OAc)2K2S2O8H2O/DMSO (1:3)1001273
20Cu(OAc)2K2S2O8H2O/DMSO (1:3)100673
21Cu(OAc)2K2S2O8H2O/DMSO (1:3)1001868
a Reaction conditions: 1a a reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), Cu catalyst (0.2 equiv.), K2S2O8 (1.5 equiv.) in solvent (2.0 mL) at 100 °C for 6 h; b isolated yield.
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MDPI and ACS Style

Zhang, H.; Liu, W.; Hu, J.; Zhang, Q.; Fang, Z.; Li, D. Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams. Catalysts 2024, 14, 797. https://doi.org/10.3390/catal14110797

AMA Style

Zhang H, Liu W, Hu J, Zhang Q, Fang Z, Li D. Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams. Catalysts. 2024; 14(11):797. https://doi.org/10.3390/catal14110797

Chicago/Turabian Style

Zhang, Hanyang, Wen Liu, Jiale Hu, Qian Zhang, Zeguo Fang, and Dong Li. 2024. "Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams" Catalysts 14, no. 11: 797. https://doi.org/10.3390/catal14110797

APA Style

Zhang, H., Liu, W., Hu, J., Zhang, Q., Fang, Z., & Li, D. (2024). Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF3-Substituted γ-Lactams. Catalysts, 14(11), 797. https://doi.org/10.3390/catal14110797

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