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Communication

Copper-Catalyzed Intramolecular Olefinic C(sp2)–H Amidation for the Synthesis of γ-Alkylidene-γ-lactams

by
Kanako Nozawa-Kumada
1,2,*,
Masahito Hayashi
1,
Eunsang Kwon
3,4,
Masanori Shigeno
1,5,
Akira Yada
2 and
Yoshinori Kondo
1
1
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Miyagi, Japan
2
Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba 305-8565, Ibaraki, Japan
3
Endowed Research Laboratory of Dimensional Integrated Nanomaterials, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Miyagi, Japan
4
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Miyagi, Japan
5
Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi 332-0012, Saitama, Japan
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(18), 6682; https://doi.org/10.3390/molecules28186682
Submission received: 11 August 2023 / Revised: 7 September 2023 / Accepted: 13 September 2023 / Published: 18 September 2023
(This article belongs to the Special Issue C-H Activation in Organic Synthesis)
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Abstract

:
Herein, we report the copper-catalyzed dehydrogenative C(sp2)–N bond formation of 4-pentenamides via nitrogen-centered radicals. This reaction provides a straightforward and efficient preparation method for γ-alkylidene-γ-lactams. Notably, we could controllably synthesize α,β-unsaturated- or α,β-saturated-γ-alkylidene-γ-lactams depending on the reaction conditions.

1. Introduction

Cross-dehydrogenative coupling (CDC) of C(sp2)–H/N–H bonds is one of the most straightforward methods for forming C(sp2)–N bonds [1,2,3,4], which are found in many pharmaceuticals, natural products, and materials [5,6,7,8]. Consequently, various approaches to accomplish CDC reactions have been reported, including aza-Wacker [9,10,11,12,13,14,15] and transition-metal-catalyzed, directing-group-assisted reactions [16,17,18,19]. The nitrogen-centered, radical-mediated reaction is considered a powerful strategy for dehydrogenative C(sp2)–N bond formation, which proceeds via the addition of N-radical species to the π-system of arenes or alkenes, following recovery of the π-system by oxidation or elimination, because it can preclude the use of precious transition-metals or the introduction and removal of directing groups. Over the past few decades, various such processes have been developed [20,21,22,23,24]; however, most of them have been applied to aryl C–H bonds, whereas olefinic C–H aminations are less explored [25].
γ-Alkylidene-γ-lactams are core structures of various natural and bioactive compounds (Scheme 1a) [26,27,28,29,30]. Several preparation methods have been developed, such as the cyclization of 4-ketoamides followed by dehydration [31,32,33], hetero Pauson–Khand reaction of ketenimines [34], cobalt-catalyzed reductive coupling of nitriles with acrylamides [35], Zn/TiCl4-mediated reductive coupling of imides with ketones [36], and photooxidative coupling of furans with amines [37,38]. Dehydrogenative C–N bond formation of 4-pentenamides is considered an efficient preparation approach because it can achieve atom- and step-economic syntheses. Recently, Poli et al. reported a palladium-catalyzed γ-methylidene-γ-lactam synthesis through the CDC between olefinic C–H and N–H bonds (Scheme 1b) [39]. However, to the best of our knowledge, this is the only example of its dehydrogenative synthesis; therefore, further development of such synthetic methods is highly desirable. Herein, we report a copper-catalyzed intramolecular dehydrogenative coupling reaction of 4-pentenamides for the synthesis of γ-alkylidene-γ-lactams via nitrogen-centered radicals (Scheme 1c). Notably, the reaction affords α,β-unsaturated- or α,β-saturated-γ-alkylidene-γ-lactams, which could be controlled by the reaction conditions. Furthermore, our method can be applied to various 4-pentenamides with methoxy, alkyl, halogen (fluoride, chloride, and bromide), trifluoromethyl, ester, and cyano substituents.

2. Results

We began our investigation of intramolecular C(sp2)–H amidation using N,5,5-triphenylpent-4-enamide 1a as the model substrate (Table 1). When the reaction was performed in the presence of CuF2 (10 mol%), 4-tert-butylpyridine (1.0 equiv), and tBuOOtBu (4.0 equiv) in 1,2-DCE at 120 °C for 18 h (condition A), 5-alkylidene-3-pyrrolin-2-one 2a was obtained in high yield (entry 1). Reactions with other copper sources, such as CuCl, CuCl2, and Cu(OAc)2, also proceeded (entry 2). Subsequent screening of pyridine derivatives revealed that 4-tert-butylpyridine afforded the best yield of 2a (entry 3). Performing the reaction in the absence of 4-tert-butylpyridine drastically decreased the yield of 2a (entry 4). Other oxidants such as tert-butyl peroxide and tert-butyl peroxyacetate lowered the yield (entry 5). On the other hand, when MnO2 was used as the oxidant, 5-alkylidene-pyrrolidin-2-one derivative 3a, which has a saturated lactam ring, was obtained with high selectivity (entry 6). Evaluation of various solvents revealed 1,2-DCE to be the most effective (entry 7). Lowering the reaction temperature to 100 °C resulted in a slightly decreased yield of the desired product 2a (entry 8). Finally, the reaction could be scaled up to 1.0 mmol to afford 2a in a good yield (entry 9).
With the optimized reaction conditions in hand, we next investigated the substrate scope for the 5-alkylidene-3-pyrrolin-2-one synthesis using tBuOOtBu as the oxidant (Scheme 2). First, we explored the scope of diarylethylene acceptors. Substrates possessing functional groups such as methyl and methoxy groups, and halogen atoms on both benzene rings afforded the desired products in moderate to high yields (2b–f). The cyclization of the substrates with tricyclic scaffolds proceeded to furnish the corresponding products (2g and 2h). Subsequently, we investigated substitution in the aniline ring and observed that the process afforded good-to-high amounts of cyclized products, regardless of the electronic properties of the aniline ring (2i–r).
Next, we investigated the synthesis of 5-alkylidene-pyrrolidin-2-ones using MnO2 as the oxidant (Scheme 3). When the reaction of 1a was performed with CuBr (10 mol%), AgBF4 (10 mol%), 4-tert-butylpyridine (25 mol%), and MnO2 (3.0 equiv) in 1,2-DCE, at 120 °C, for 24 h (condition B) [40,41,42], 5-alkylidene-pyrrolidin-2-one 3a was obtained in a high yield (for details, see Supplementary Materials). Using these optimized conditions, we then explored the scope and generality of the 5-alkylidene-pyrrolidin-2-one synthesis. Substrates with various functional groups on the diarylethylene moieties were first examined and afforded the corresponding cyclized products with high selectivities (3b–e). Subsequently, the reaction of amide bearing tricyclic dibenzo[a,d]cycloheptene scaffold proceeded smoothly (3h). Finally, the effect of aryl groups on the nitrogen atoms was investigated. Substrates possessing benzene derivatives on their amide nitrogen atoms smoothly underwent cyclization (3i–r). This process could also be applied to N-benzothiazole-substituted amide, which, however, afforded a low yield (3s).
Having studied the scope of the reaction, we next conducted experiments to obtain an insight into the reaction mechanism (Scheme 4). First, under both optimized conditions, the reactions were performed in the presence of the radical scavengers 2,6-di-tert-butyl-4-methylphenol (BHT) or hydroquinone, which led to a significant decrease in the yield of 2a (condition A) or 3a (condition B) (Scheme 4a). These results suggest that the reactions proceeded via radical processes. Next, to investigate the possibility of saturated-r-lactam 3a acting as an intermediate for 2a, the reaction using 3a as a substrate was conducted under condition A (Scheme 4b). Consequently, 2a was obtained in 32% yield, indicating that 3a is one of the intermediates in the synthesis of 2a. In contrast, we recovered the starting material 3a under condition B. Furthermore, regarding α,β-unsaturated-γ-alkylidene-γ-lactam 2 synthesis, we shortened the reaction time to unveil the reaction intermediate, and aminochlorinated product 4a was obtained in a good yield (Scheme 4c). The structure of 4a was confirmed by X-ray crystallographic analysis (for details, see Supplementary Materials). Contrary, the reaction under condition B for 3 h produced only 6% of 4a. Subsequently, the reaction starting from 4a under condition A proceeded smoothly, suggesting that 4a is a possible intermediate for the synthesis of α,β-unsaturated-γ-alkylidene-γ-lactam 2a (Scheme 4d). Additionally, transformation of 4a under condition B also proceeded to afford 2a in good yield. From these results, we assume that the preference for either 2 or 3 is determined by whether aminochlorinated compound 4 is formed in situ.
Based on these experimental results, a plausible mechanism is proposed for copper-catalyzed intramolecular olefinic C(sp2)–H amidation (Scheme 5). For the formation of 5-alkylidene-3-pyrrolin-2-ones 2 under condition A, the nitrogen-centered radical A is initially generated by the CuII species [43,44,45]. It subsequently undergoes addition to an alkene moiety present in the substrate to afford the dibenzylic radical species B. For the next step, there are two possibilities: In the first, B is chlorinated under condition A to form the aminochlorinated product 4a [46,47,48,49], and. subsequent HCl elimination and further oxidation results in the formation of 2a. In the second, 3a is generated by oxidation and deprotonation of B, and further oxidation of 3a occurs to provide 2a [50,51,52]. On the other hand, under condition B, 3a is formed via oxidation and deprotonation of B as in condition A, however, no further transformation of 3a occurs, resulting in the formation of 3a as the major product. The detailed mechanism is unclear at present and needs to be clarified through further investigation.

3. Materials and Methods

3.1. Materials

Materials were purchased from Tokyo Kasei Co. (Tokyo, Japan), Sigma-Aldrich Inc. (St. Louis, MO, USA) and other commercial suppliers, and were used as received. Flash column chromatography was performed with Kanto silica gel 60 N (spherical, neutral, 70–230 mesh). Melting points were measured with a Yazawa micro melting point apparatus and uncorrected. IR spectra were recorded on a SHIMADZU IRAffinity. 1H NMR spectra were recorded on a JEOL JNMAL400 (400 MHz) spectrometer or a JEOL ECA600 (600 MHz) spectrometer. Chemical shifts are expressed in δ (parts per million, ppm) values and coupling constants are expressed in herts (Hz). 1H NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal (CDCl3: 7.26 ppm, DMSO-d6: 2.49 ppm). 13C NMR spectra were referenced to a solvent signal (CDCl3: 77.0 ppm, DMSO-d6: 39.5 ppm). 19F NMR spectra were referenced to 4-fluorotoluene as an internal standard (−118.0 ppm). The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd, = double doublet, m = multiplet, and br.s. = broad singlet. Low- and high-resolution mass spectra (LRMS and HRMS) were obtained from Mass Spectrometry Resource, Graduate School of Pharmaceutical Sciences, Tohoku University, on a JEOL JMS-DX 303 and JMS700/JMS-T 100 GC spectrometer. The Bruker D8 VENTURE X-ray diffractometer was used to determine the structure of the grown crystals.

3.2. General Procedure for the Synthesis of 5-Alkylidene-pyrrolin-2-ones

In a glove box, amide 1 (0.20 mmol), CuF2 (2.0 mg, 0.020 mmol), 4-tert-butylpyridine (29.3 μL, 0.020 mmol), tBuOOtBu (147.0 μL, 0.80 mmol), and 1,2-dichloroethane (2.5 mL) were added to a sealed tube. The mixture was stirred at 120 °C for 18 h. The reaction was diluted with water (10 mL) and extracted with chloroform (10 mL × 3). The organic layers were washed with brine (10 mL) and dried over MgSO4. The solvent was removed under a reduced pressure and the residue was purified by SiO2 column chromatography.

3.3. General Procedure for the Synthesis of 5-Alkylidene-pyrrolidin-2-ones

In a glove box, amide 1 (0.20 mmol), CuBr (2.8 mg, 0.020 mmol), AgBF4 (3.8 mg, 0.020 mmol), tert-butylpyridine (7.4 μL, 0.050 mmol), MnO2 (52.2 mg, 0.60 mmol), and 1,2-dichloroethane (1.5 mL) were added to a sealed tube. The mixture was stirred at 120 °C for 24 h. After the reaction, the mixture was filtered through Celite and a SiO2 pad with AcOEt, and then the solvent was removed under a reduced pressure. The residue was purified by SiO2 column chromatography.

3.4. Spectroscopic Data of Products

5-(Diphenylmethylene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2a). Obtained as yellow needles in 85% (55.0 mg, 0.20 mmol scale), 87% (286.6 mg, 1.0 mmol scale), recrystallized from DCM/hexane, mp. 160–163 °C. 1H NMR (400 MHz, CDCl3/TMS) δ (ppm): 7.38–7.36 (3H, m), 7.26–7.23 (2H, m), 7.21 (1H, d, J = 5.8 Hz), 7.00–6.83 (10H, m), 6.28 (1H, d, J = 5.4 Hz); 13C{1H} NMR (100 MHz, CDCl3/TMS) δ (ppm): 171.8, 140.5, 140.3, 138.1, 137.9, 135.8, 131.6, 130.94, 130.89, 128.4, 128.0, 127.9, 127.7, 127.2, 127.1, 126.0, 121.7; LRMS (EI) m/z: 323 (M+); HRMS (EI-TOF) Calcd. for C23H17NO: 323.1310, found: 323.1286; IR (neat): 3052, 1691, 1683, 1498, 1443, 1370, 1213, 1203, 1163, 1073, 968, 801, 774, 765, 756 cm−1.
5-(Bis(4-methoxyphenyl)methylene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2b). Obtained as red crystals in 80% (61.5 mg), recrystallized from DCM/hexane, mp. 177–178 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.19–7.17 (3H, m), 7.01 (2H, t, J = 7.6 Hz), 6.97–6.94 (3H, m), 6.90 (2H, d, J = 8.9 Hz), 6.77 (2H, d, J = 8.9 Hz), 6.42 (2H, d, J = 8.9 Hz), 6.23 (1H, d, J = 5.5 Hz), 3.85 (3H, s), 3.66 (3H, s); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.9, 160.1, 159.3, 140.3, 136.8, 136.1, 133.1, 132.5, 131.0, 130.6, 127.8, 127.0, 125.73, 125.72, 120.6, 113.5, 112.7, 55.3, 55.2; LRMS (EI) m/z: 383 (M+); HRMS (EI-TOF) Calcd. for C25H21NO3: 383.1521, found: 383.1539; IR (neat): 1675, 1604, 1508, 1498, 1252, 1179, 1028, 969, 831 cm−1.
5-(Di-p-tolylmethylene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2c). Obtained as colorless needles in 60% (42.4 mg), recrystallized from DCM/hexane, mp. 161–162 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 7.21 (2H, d, J = 8.2 Hz), 7.18 (1H, d, J = 5.9 Hz), 7.11 (2H, d, J = 8.3 Hz), 6.99 (2H, t, J = 7.2 Hz), 6.94–6.91 (3H, m), 6.70 (2H, d, J = 8.2 Hz), 6.67 (2H, d, J = 8.2 Hz), 6.30 (1H, d, J = 5.9 Hz), 2.34 (3H, s), 2.07 (3H, s); 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm): 171.0, 140.6, 138.1, 137.5, 137.3, 137.1, 136.0, 135.1, 131.4, 130.6, 130.3, 128.8, 127.7, 127.6, 127.2, 125.5, 121.0, 20.8, 20.7; LRMS (EI) m/z: 351 (M+); HRMS (EI-TOF) Calcd. for C25H21NO: 351.1623, found: 351.1606; IR (neat): 1688, 1497, 1371, 1300, 1209, 1182, 969, 823, 802 cm−1.
5-(Bis(4-fluorophenyl)methylene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2d). Obtained as yellow crystals in 82% (58.9 mg), recrystallized from DCM/hexane, mp. 153–155 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.21 (2H, dd, J = 8.6, 5.2 Hz), 7.17 (1H, d, J = 5.5 Hz), 7.08 (2H, t, J = 8.6 Hz), 7.03 (2H, t, J = 7.6 Hz), 6.98 (1H, t, J = 7.6 Hz), 6.95–6.93 (2H, m), 6.80 (2H, dd, J = 8.9, 5.5 Hz), 6.59 (2H, t, J = 8.9 Hz), 6.29 (1H, d, J = 5.5 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.6, 163.0 (d, JC–F = 249.3 Hz), 162.1 (d, JC–F = 249.3 Hz), 139.8, 138.2, 136.4 (d, JC–F = 2.9 Hz), 135.7, 133.9 (d, JC–F = 2.9 Hz), 133.2 (d, JC–F = 8.6 Hz), 132.6 (d, JC–F = 8.6 Hz), 128.2, 128.1, 127.1, 126.3, 122.1, 115.3 (d, JC–F = 21.5 Hz), 114.4 (d, JC–F = 22.9 Hz); 19F NMR (565 MHz, CDCl3) δ (ppm): −111.7, −111.9; LRMS (EI) m/z: 359 (M+); HRMS (EI-TOF) Calcd. for C23H15F2NO: 359.1122, found: 359.1110; IR (neat): 3039, 1688, 1594, 1505, 1497, 1366, 1305, 1231, 1156, 1101, 969, 844 cm−1.
5-(Bis(4-chlorophenyl)methylene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2e). Obtained as yellow crystals in 70% (54.6 mg), recrystallized from DCM/hexane, mp. 206–208 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.36 (2H, d, J = 8.2 Hz), 7.18–7.16 (3H, m), 7.05–6.99 (3H, m), 6.93–6.92 (2H, m), 6.86 (2H, d, J = 8.3 Hz), 6.74 (2H, d, J = 8.9 Hz), 6.31 (1H, d, J = 5.5 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.5, 139.6, 138.7, 138.5, 136.0, 135.5, 134.9, 133.9, 132.7, 132.0, 128.5, 128.2, 127.6, 127.5, 127.1, 126.3, 122.4; LRMS (EI) m/z: 391 (M+); HRMS (EI-TOF) Calcd. for C23H1535Cl2NO: 391.0531, found: 391.0503; IR (neat): 3063, 1689, 1595, 1498, 1489, 1216, 1087, 1011, 806 cm−1.
5-(Bis(4-(trifluoromethyl)phenyl)methylene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2f). Obtained as yellow crystals in 63% (58.3 mg), recrystallized from DCM/hexane, mp. 168–170 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.66 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.21 (1H, d, J = 6.2 Hz), 7.14 (2H, d, J = 8.2 Hz), 7.02–6.95 (3H, m), 6.93–6.90 (4H, m), 6.37 (1H, d, J = 5.5 Hz); 13C{1H, 19F} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.3, 143.4, 140.9, 140.0, 139.4, 135.3, 131.8, 130.9, 130.7, 129.8, 128.3, 127.3, 126.7, 126.4, 125.4, 124.3, 123.9, 123.6, 123.4; 19F NMR (565 MHz, CDCl3) δ (ppm): −62.1, −62.5; LRMS (EI) m/z: 459 (M+); HRMS (EI-TOF) Calcd. for C25H15F6NO: 459.1058, found: 459.1048; IR (neat): 1696, 1612, 1322, 1155, 1121, 1065, 810 cm−1.
1-Phenyl-5-(9H-xanthen-9-ylidene)-1,5-dihydro-2H-pyrrol-2-one (2g). Obtained as yellow crystals in 25% (16.4 mg), recrystallized from DCM/hexane, mp. 180–183 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 8.02 (1H, d, J = 6.0 Hz), 7.62 (1H, dd, J = 7.5, 1.5 Hz), 7.40–7.37 (1H, m), 7.30–7.25 (2H, m), 7.07–7.02 (4H, m), 6.99 (1H, td, J = 7.7, 1.5 Hz), 6.92 (2H, dd, J = 8.0, 1.5 Hz), 6.70 (1H, dd, J = 7.5, 1.5 Hz), 6.40 (1H, d, J = 6.0 Hz), 6.38–6.35 (1H, m); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.7, 154.2, 153.2, 138.8, 136.5, 134.4, 128.9, 128.7, 128.6, 128.1, 127.5, 126.6, 126.3, 124.2, 123.8, 122.5, 122.0, 121.6, 116.9, 116.3, 115.2; LRMS (EI) m/z: 337 (M+); HRMS (EI-TOF) Calcd. for C23H15NO2: 337.1103, found: 337.1096; IR (neat): 1684, 1593, 1495, 1447, 1199, 966, 872 cm−1.
5-(5H-Dibenzo[a,d][7]annulen-5-ylidene)-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (2h). Obtained as yellow crystals in 78% (54.0 mg), recrystallized from DCM/hexane, mp. 235–236 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.40–7.38 (1H, m), 7.35–7.32 (3H, m), 7.28–7.18 (3H, m), 7.08 (1H, d, J = 8.3 Hz), 6.99–6.89 (4H, m), 6.70–6.65 (3H, m), 6.29–6.24 (2H, m); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.3, 138.4, 136.8, 136.3, 135.7, 135.3, 134.8, 133.5, 131.2, 130.9, 129.3, 128.5, 128.1, 128.0, 127.8, 127.54, 127.49, 127.4, 127.3, 126.9, 126.6, 126.3, 122.6; LRMS (EI) m/z: 347 (M+); HRMS (EI-TOF) Calcd. for C25H17NO: 347.1310, found: 347.1286; IR (neat): 1690, 1496, 1371, 1210, 1167, 786 cm−1.
5-(Diphenylmethylene)-1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (2i). Obtained as yellow crystals in 77% (54.1 mg), recrystallized from DCM/hexane, mp. 133–134 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.37–7.35 (3H, m), 7.23 (2H, dd, J = 7.9, 1.7 Hz), 7.18 (1H, d, J = 6.2 Hz), 6.99–6.96 (1H, m), 6.91 (2H, t, J = 7.6 Hz), 6.86–6.82 (4H, m), 6.53–6.51 (2H, m), 6.27 (1H, d, J = 6.2 Hz), 3.66 (3H, s); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 172.0, 157.6, 140.6, 139.9, 138.3, 137.9, 131.6, 130.9, 130.6, 128.8, 128.33, 128.28, 128.0, 127.6, 127.2, 121.7, 113.4, 55.3; LRMS (EI) m/z: 353 (M+); HRMS (EI-TOF) Calcd. for C24H19NO2: 353.1416, found: 353.1410; IR (neat): 3052, 1690, 1613, 1512, 1443, 1248, 1159, 1026, 830, 806 cm−1.
5-(Diphenylmethylene)-1-(p-tolyl)-1,5-dihydro-2H-pyrrol-2-one (2j). Obtained as yellow crystals in 81% (54.4 mg), recrystallized from DCM/hexane, mp. 103–105 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.37–7.35 (3H, m), 7.24 (2H, dd, J = 7.9, 1.7 Hz), 7.18 (1H, d, J = 6.2 Hz), 6.95 (1H, t, J = 7.5 Hz), 6.88 (2H, t, J = 7.5 Hz), 6.83–6.81 (4H, m), 6.77 (2H, d, J = 8.2 Hz), 6.26 (1H, d, J = 6.2 Hz), 2.14 (3H, s); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.9, 140.7, 140.0, 138.3, 138.0, 135.7, 133.2, 131.6, 130.9, 130.7, 128.5, 128.4, 128.0, 127.4, 127.1, 127.0, 121.8, 20.8; LRMS (EI) m/z: 337 (M+); HRMS (EI-TOF) Calcd. for C24H19NO: 337.1467, found: 337.1441; IR (neat): 3030, 1690, 1593, 1515, 1489, 1446, 1374, 1218, 1162, 971, 824 cm−1.
5-(Diphenylmethylene)-1-(4-isopropylphenyl)-1,5-dihydro-2H-pyrrol-2-one (2k). Obtained as orange crystals in 81% (58.9 mg), recrystallized from DCM/hexane, mp. 121–124 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.37–7.34 (3H, m), 7.25–7.23 (2H, m), 7.19 (1H, d, J = 5.5 Hz), 6.91 (1H, t, J = 7.2 Hz), 6.86–6.78 (8H, m), 6.27 (1H, d, J = 6.2 Hz), 2.69 (1H, sep, J = 6.9 Hz), 1.09 (6H, d, J = 6.9 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.8, 146.7, 140.7, 139.9, 138.2, 137.9, 133.3, 131.6, 130.8, 130.7, 128.3, 128.0, 127.5, 127.1, 127.0, 125.9, 121.7, 33.6, 23.8; LRMS (EI) m/z: 365 (M+); HRMS (EI-TOF) Calcd. for C26H23NO: 365.1780, found: 365.1752; IR (neat): 2958, 2863, 1692, 1371, 1155, 805 cm−1.
5-(Diphenylmethylene)-1-(4-fluorophenyl)-1,5-dihydro-2H-pyrrol-2-one (2l). Obtained as yellow crystals in 78% (53.3 mg), recrystallized from DCM/hexane, mp. 153–155 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.39–7.36 (3H, m), 7.25–7.21 (3H, m), 7.01 (1H, t, J = 7.2 Hz), 6.94–6.90 (4H, m), 6.83 (2H, d, J = 6.9 Hz), 6.68 (2H, t, J = 8.6 Hz), 6.27 (1H, d, J = 6.2 Hz); 13C{1H, 19F} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.9, 160.6, 140.4, 140.3, 138.1, 137.9, 131.9, 131.7, 131.03, 130.95, 128.8, 128.6, 128.2, 128.0, 127.4, 121.7, 114.8; 19F NMR (565 MHz, CDCl3) δ (ppm): −115.4; LRMS (EI) m/z: 341 (M+); HRMS (EI-TOF) Calcd. for C23H16FNO: 341.1216, found: 341.1239; IR (neat): 1693, 1600, 1506, 1490, 1382, 1216, 974, 838, 808, 738 cm−1.
1-(4-Chlorophenyl)-5-(diphenylmethylene)-1,5-dihydro-2H-pyrrol-2-one (2m). Obtained as yellow crystals in 88% (63.2 mg), recrystallized from DCM/hexane, mp. 128–130 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.39–7.36 (3H, m), 7.25–7.22 (3H, m), 7.03 (1H, t, J = 7.2 Hz), 6.95–6.92 (4H, m), 6.89–6.87 (2H, m), 6.83 (2H, d, J = 6.9 Hz), 6.27 (1H, d, J = 6.2 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.5, 140.4, 140.2, 137.8, 137.7, 134.5, 131.62, 131.57, 131.2, 130.9, 128.6, 128.2, 128.1, 127.99, 127.97, 127.4, 121.6; LRMS (EI) m/z: 357 (M+); HRMS (EI-TOF) Calcd. for C23H1635ClNO: 357.0920, found: 357.0910; IR (neat): 1688, 1593, 1554, 1493, 1446, 1374, 1203, 1089, 971, 833, 798 cm−1.
1-(4-Bromophenyl)-5-(diphenylmethylene)-1,5-dihydro-2H-pyrrol-2-one (2n). Obtained as yellow crystals in 89% (71.4 mg), recrystallized from DCM/hexane, mp. 149–151 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.39–7.36 (3H, m), 7.25–7.22 (3H, m), 7.10 (2H, d, J = 8.2 Hz), 7.04 (1H, t, J = 7.6 Hz), 6.94 (2H, t, J = 7.9 Hz), 6.83–6.81 (4H, m), 6.27 (1H, d, J = 5.5 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.5, 140.5, 140.2, 137.8, 137.6, 135.0, 131.6, 131.2, 130.93, 130.89, 128.61, 128.58, 128.1, 128.0, 127.4, 121.7, 119.5; LRMS (EI) m/z: 401 (M+); HRMS (EI-TOF) Calcd. for C23H1679BrNO: 401.0415, found: 401.0427; IR (neat): 3068, 1684, 1489, 1162, 1068, 1015, 831, 798 cm−1.
5-(Diphenylmethylene)-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-one (2o). Obtained as colorless needles in 46% (35.8 mg), recrystallized from DCM/hexane, mp. 136–137 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.41–7.37 (3H, m), 7.27–7.26 (3H, m), 7.23 (2H, d, J = 8.9 Hz), 7.06 (2H, d, J = 8.2 Hz), 6.97 (1H, t, J = 7.2 Hz), 6.90 (2H, t, J = 7.6 Hz), 6.82 (2H, d, J = 7.6 Hz), 6.30 (1H, d, J = 5.5 Hz); 13C{1H, 19F} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.3, 140.8, 140.1, 139.1, 137.8, 137.5, 131.7, 131.5, 130.8, 128.8, 128.24, 128.19, 127.9, 127.5, 127.2, 124.9, 123.8, 121.7; 19F NMR (565 MHz, CDCl3) δ (ppm): −62.1; LRMS (EI) m/z: 391 (M+); HRMS (EI-TOF) Calcd. for C24H16F3NO (M+): 391.1184, found: 391.1174; IR (neat): 1691, 1379, 1322, 1112, 1063, 975, 853, 800 cm−1.
4-(2-(Diphenylmethylene)-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)benzonitrile (2p). Obtained as yellow crystals in 73% (51.0 mg), recrystallized from DCM/hexane, mp. 178–179 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.43–7.38 (3H, m), 7.29–7.25 (5H, m), 7.09–7.08 (2H, m), 7.03 (1H, t, J = 7.2 Hz), 6.94 (2H, t, J = 7.9 Hz), 6.86–6.84 (2H, m), 6.29 (1H, d, J = 6.2 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.0, 141.2, 140.0, 139.8, 137.8, 137.0, 131.8, 131.7, 131.6, 130.9, 128.9, 128.5, 128.3, 127.6, 127.2, 121.5, 118.5, 109.0; LRMS (EI) m/z: 348 (M+); HRMS (EI-TOF) Calcd. for C24H16N2O: 348.1263, found: 348.1263; IR (neat): 2226, 1690, 1600, 1506, 1367, 1207, 1159, 970, 845, 799 cm−1.
Methyl 4-(2-(diphenylmethylene)-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate (2q). Obtained as colorless needles in 78% (58.9 mg), recrystallized from DCM/hexane, mp. 193–195 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.67 (2H, d, J = 8.2 Hz), 7.41–7.38 (3H, m), 7.27–7.25 (3H, m), 7.04 (2H, d, J = 8.2 Hz), 6.94 (1H, t, J = 7.2 Hz), 6.90 (2H, t, J = 7.6 Hz), 6.85 (2H, d, J = 6.8 Hz), 6.28 (1H, d, J = 6.2 Hz), 3.84 (3H, s); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.4, 166.4, 140.8, 140.2, 140.1, 137.9, 137.5, 131.65, 131.58, 131.57, 130.9, 129.3, 128.7, 128.2, 127.5, 127.1, 126.5, 121.6, 52.0; LRMS (EI) m/z: 381 (M+); HRMS (EI-TOF) Calcd. for C25H19NO3: 381.1365, found: 381.1341; IR (neat): 3062, 1722, 1696, 1601, 1507, 1437, 1361, 1275, 1167, 1102, 1072, 969, 863, 802 cm−1.
1-(3-Bromophenyl)-5-(diphenylmethylene)-1,5-dihydro-2H-pyrrol-2-one (2r). Obtained as yellow needles in 85% (68.2 mg), recrystallized from DCM/hexane, mp. 143–145 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.39–7.36 (3H, m), 7.25–7.23 (3H, m), 7.04 (1H, d, J = 8.2 Hz), 7.01–6.96 (5H, m), 6.89 (1H, t, J = 7.9 Hz), 6.86 (2H, d, J = 6.8 Hz), 6.27 (1H, d, J = 5.5 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 171.4, 140.5, 140.2, 137.8, 137.5, 136.9, 131.6, 131.3, 130.6, 130.2, 129.1, 128.9, 128.6, 128.14, 128.10, 127.4, 125.8, 121.6, 121.3; LRMS (EI) m/z: 401 (M+); HRMS (EI-TOF) Calcd. for C23H1679BrNO (M+): 401.0415, found: 401.0438; IR (neat): 1690, 1587, 1476, 1364, 1201, 1152, 980, 802 cm−1.
5-(Diphenylmethylene)-1-phenylpyrrolidin-2-one (3a). Obtained as colorless plates in 91% (59.0 mg), recrystallized from DCM/hexane, mp. 146–148 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.31–7.29 (2H, m), 7.25–7.22 (1H, m), 7.19–7.18 (2H, m), 7.00–6.96 (4H, m), 6.90–6.88 (1H, m), 6.83–6.81 (3H, m), 6.72–6.71 (2H, m), 2.99–2.97 (2H, m), 2.71–2.68 (2H, m); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.3, 142.1, 139.2, 137.9, 136.1, 130.1, 130.0, 128.2, 127.9, 127.1, 126.7, 126.2, 126.0, 125.9, 120.2, 30.9, 28.3; LRMS (EI) m/z: 325 (M+); HRMS (EI-TOF) Calcd. for C23H19NO: 325.1467, found: 325.1456; IR (neat): 3046, 1723, 1620, 1595, 1495, 1359, 1160, 1027, 773, 751 cm−1.
5-(Bis(4-methoxyphenyl)methylene)-1-phenylpyrrolidin-2-one (3b). Obtained as yellow crystals in 61% (46.8 mg), recrystallized from DCM/hexane, mp. 164–166 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.09 (2H, d, J = 8.9 Hz), 6.99–6.98 (4H, m), 6.91–6.90 (1H, m), 6.84 (2H, d, J = 8.9 Hz), 6.61 (2H, d, J = 8.9 Hz), 6.36 (2H, d, J = 8.9 Hz), 3.80 (3H, s), 3.62 (3H, s), 2.96 (2H, t, J = 7.7 Hz), 2.68 (2H, t, J = 7.7 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.3, 158.3, 157.7, 136.7, 136.1, 134.6, 132.0, 131.1, 131.0, 127.9, 126.1, 125.9, 119.5, 113.5, 112.6, 55.2, 55,1, 31.1, 28.4; LRMS (EI) m/z: 385 (M+); HRMS (EI-TOF) Calcd. for C25H23NO3: 385.1678, found: 385.1706; IR (neat): 2969, 2835, 1713, 1606, 1508, 1358, 1179, 1027, 829, 761 cm−1.
5-(Di-p-tolylmethylene)-1-phenylpyrrolidin-2-one (3c). Obtained as colorless needles in 99% (69.4 mg, 3c:2c = 93:7), recrystallized from DCM/hexane, mp. 208–211 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.10 (2H, d, J = 8.2 Hz), 7.06 (2H, d, J = 8.2 Hz), 6.98–6.95 (4H, m), 6.90–6.87 (1H, m), 6.61 (2H, d, J = 8.2 Hz), 6.58 (2H, d, J = 8.2 Hz), 2.97 (2H, t, J = 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz), 2.34 (3H, s), 2.09 (3H, s); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.3, 139.3, 137.3, 136.4, 136.3, 136.2, 135.5, 129.9, 129.8, 128.8, 127.85, 127.76, 126.2, 125.7, 120.2, 31.1, 28.4, 21.1, 20.9; LRMS (EI) m/z: 353 (M+); HRMS (EI-TOF) Calcd. for C25H23NO: 353.1780, found: 353.1775; IR (neat): 3019, 2927, 1732, 1636, 1496, 1369, 1228, 1154, 815 cm−1.
5-(Bis(4-fluorophenyl)methylene)-1-phenylpyrrolidin-2-one (3d). Obtained as colorless crystals in 80% (58.2 mg, 3d:2d = 95:5), recrystallized from DCM/hexane, mp. 179–181 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.14–7.12 (2H, m), 7.03–6.94 (7H, m), 6.67–6.64 (2H, m), 6.52 (2H, t, J = 8.6 Hz), 2.95 (2H, t, J = 7.9 Hz), 2.70 (2H, t, J = 7.9 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.2, 161.6 (1JC–F = 246.4 Hz), 161.0 (1JC–F = 246.4 Hz), 138.4, 137.8 (4JC–F = 4.3 Hz), 135.9, 135.1 (4JC–F = 2.9 Hz), 131.55 (3 JC–F = 7.2 Hz), 131.48 (3JC–F = 8.6 Hz), 128.1, 126.4, 126.3, 117.8, 115.2 (2JC–F = 21.5 Hz), 114.1 (2JC–F = 21.5 Hz), 30.8, 28.2; 19F NMR (565 MHz, CDCl3) δ (ppm): −114.5, −115.2; LRMS (EI) m/z: 361 (M+); HRMS (EI-TOF) Calcd. for C23H17F2NO: 361.1278, found: 361.1262; IR (neat): 3040, 1736, 1632, 1598, 1505, 1370, 1293, 1153, 831, 758 cm−1.
5-(Bis(4-chlorophenyl)methylene)-1-phenylpyrrolidin-2-one (3e). Obtained as colorless needles in 82% (65.5 mg, 3e:2e = 94:6), recrystallized from DCM/hexane, mp. 204–206 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.28 (2H, d, J = 8.2 Hz), 7.09 (2H, d, J = 8.2 Hz), 7.04–7.01 (2H, m), 6.98 (1H, d, J = 6.9 Hz), 6.95 (2H, d, J = 7.6 Hz), 6.79 (2H, d, J = 8.2 Hz), 6.61 (2H, d, J = 8.2 Hz), 2.96 (2H, t, J = 7.7 Hz), 2.71 (2H, t, J = 7.7 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.1, 140.0, 139.1, 137.3, 135.8, 132.7, 132.0, 131.30, 131.26, 128.5, 128.2, 127.4, 126.5, 126.3, 117.4, 30.7, 28.2; LRMS (EI) m/z: 393 (M+); HRMS (EI-TOF) Calcd. for C23H1735Cl2NO: 393.0687, found: 393.0671; IR (neat): 3064, 2944, 1732, 1612, 1488, 1355, 1156, 1012, 828, 756 cm−1.
5-(5H-Dibenzo[a,d][7]annulen-5-ylidene)-1-phenylpyrrolidin-2-one (3h). Obtained as colorless crystals in 66% (46.3 mg), recrystallized from DCM/hexane, mp. 199–200 °C. 1H NMR (600 Hz, DMSO-d6) δ (ppm): 7.42–7.36 (3H, m), 7.27–7.24 (1H, m), 7.02–6.89 (6H, m), 6.83–6.56 (5H, m), 3.12–3.08 (1H, m), 2.70–2.64 (1H, m), 2.45–2.41 (1H, m), 2.26–2.21 (1H, m); 13C{1H} NMR (150 Hz, DMSO-d6), δ (ppm): 176.3, 138.3, 137.1, 136.8, 136.4, 134.9, 133.8, 131.3, 130.9, 128.9, 128.7, 128.3, 128.1, 127.8, 127.3, 127.2, 127.0, 126.4, 126.3, 125.6, 114.1, 28.7, 24.2; LRMS (EI) m/z: 349 (M+); HRMS (EI-TOF) Calcd. for C25H19NO: 349.1467, found: 349.1465; IR (neat): 3017, 1717, 1636, 1497, 1370, 1239, 1171, 803, 738 cm−1.
5-(Diphenylmethylene)-1-(4-methoxyphenyl)pyrrolidin-2-one (3i). Obtained as colorless needles in 76% (54.7 mg, 3i:2i = 93:7), recrystallized from DCM/hexane, mp. 158–161 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.29 (2H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7.2 Hz), 7.18 (2H, d, J = 6.9 Hz), 6.88–6.84 (5H, m), 6.71–6.70 (2H, m), 6.50 (2H, d, J = 8.9 Hz), 3.65 (3H, s), 2.96 (2H, t, J = 7.9 Hz), 2.67 (2H, t, J = 7.9 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.6, 157.6, 142.2, 139.1, 138.2, 130.2, 129.9, 129.1, 128.2, 127.5, 127.1, 126.6, 125.9, 119.7, 113.4, 55.4, 30.7, 28.1; LRMS (EI) m/z: 355 (M+); HRMS (EI-TOF) Calcd. for C24H21NO2: 355.1572, found: 355.1549; IR (neat): 3257, 1700, 1636, 1511, 1444, 1242, 1031, 741 cm−1.
5-(Diphenylmethylene)-1-(p-tolyl)pyrrolidin-2-one (3j). Obtained as yellow oil in 92% (62.7 mg, 3j:2j = 93:7). 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.30 (2H, t, J = 7.5 Hz), 7.22 (1H, tt, J = 7.4, 1.5 Hz), 7.19–7.17 (2H, m), 6.85–6.80 (5H, m), 6.76 (2H, d, J = 8.1 Hz), 6.71–6.69 (2H, m), 2.98–2.95 (2H, m), 2.69–2.67 (2H, m), 2.13 (3H, s); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.5, 142.2, 139.2, 138.1, 135.8, 133.5, 130.2, 130.0, 128.5, 128.2, 127.1, 126.6, 126.2, 125.7, 119.9, 30.8, 28.2, 20.8; LRMS (EI) m/z: 339 (M+); HRMS (EI-TOF) Calcd. for C24H21NO: 339.1623, found: 339.1617; IR (neat): 3057, 1718, 1631, 1512, 1364, 1229, 1167, 1030, 816, 751 cm−1.
5-(Diphenylmethylene)-1-(4-isopropylphenyl)pyrrolidin-2-one (3k). Obtained as colorless oil in 99% (72.5 mg, 3k:2k = 92:8). 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.29 (2H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7.6 Hz), 7.18 (2H, d, J = 7.6 Hz), 6.85 (2H, d, J = 8.9 Hz), 6.80–6.79 (5H, m), 6.67 (2H, dd, J = 6.5, 3.1 Hz), 2.96 (2H, t, J = 7.9 Hz), 2.70–2.65 (3H, m), 1.09 (6H, d, J = 6.8 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.5, 146.8, 142.2, 139.1, 138.1, 133.6, 130.1, 129.9, 128.2, 127.0, 126.5, 126.3, 126.0, 125.8, 119.7, 33.7, 30.7, 28.1, 23.9; LRMS (EI) m/z: 367 (M+); HRMS (EI-TOF) Calcd. for C26H25NO: 367.1936, found: 367.1925; IR (neat): 3018, 2959, 1723, 1630, 1512, 1364, 1300, 1229, 1167, 832 cm−1.
5-(Diphenylmethylene)-1-(4-fluorophenyl)pyrrolidin-2-one (3l). Obtained as colorless needle in 92% (63.4 mg, 3l:2l = 93:7), recrystallized from DCM/hexane, mp. 128–130 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.32–7.29 (2H, m), 7.25–7.22 (1H, m), 7.18–7.16 (2H, m), 6.96–6.93 (2H, m), 6.91–6.85 (3H, m), 6.72–6.70 (2H, m), 6.68–6.65 (2H, m), 3.00–2.97 (2H, m), 2.70–2.68 (2H, m); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.4, 160.5 (1JC–F = 245.0 Hz), 141.9, 139.1, 137.9, 132.1 (4JC–F = 2.9 Hz) 130.2, 129.9, 128.2, 128.0 (3JC–F = 8.6 Hz), 127.3, 126.8, 126.2, 120.2, 114.8 (2JC–F = 22.9 Hz), 30.8, 28.2; 19F NMR (565 MHz, CDCl3) δ (ppm): −115.1; LRMS (EI) m/z: 343 (M+); HRMS (EI-TOF) Calcd. For C23H18FN: 343.1372, found: 343.1352; IR (neat): 3058, 1724, 1633, 1604, 1507, 1368, 1299, 1228, 1153, 910, 752 cm−1.
1-(4-Chlorophenyl)-5-(diphenylmethylene)pyrrolidin-2-one (3m). Obtained as colorless needles in 76% (55.4 mg), recrystallized from DCM/hexane, mp. 165–167 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.31 (2H, t, J = 7.6 Hz), 7.25–7.22 (1H, m), 7.18–7.17 (2H, m), 6.94–6.86 (7H, m), 6.72–6.70 (2H, m), 2.98 (2H, t, J = 7.9 Hz), 2.69 (2H, t, J = 7.9 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.1, 141.7, 139.0, 137.6, 134.6, 131.4, 130.1, 129.9, 128.2, 128.0, 127.42, 127.38, 126.8, 126.2, 120.5, 30.9, 28.2; LRMS (EI) m/z: 359 (M+); HRMS (EI-TOF) Calcd. for C23H1835ClNO: 359.1077, found: 359.1092; IR (neat): 3076, 2929, 1719, 1636, 1492, 1364, 1300, 1233, 1165, 1088, 833 cm−1.
1-(4-Bromophenyl)-5-(diphenylmethylene)pyrrolidin-2-one (3n). Obtained as colorless needles in 80% (64.7 mg, 3n:2n = 96:4), recrystallized from DCM/hexane, mp. 188–189 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.30 (2H, t, J = 7.6 Hz), 7.25–7.24 (1H, m), 7.17 (2H, d, J = 7.5 Hz), 7.08 (2H, d, J = 8.9 Hz), 6.91 (1H, t, J = 9.6 Hz), 6.87–6.85 (4H, m), 6.70 (2H, d, J = 7.6 Hz), 2.98 (2H, t, J = 7.9 Hz), 2.68 (2H, t, J = 7.9 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.1, 141.7, 139.0, 137.5, 135.1, 131.0, 130.1, 129.9, 128.2, 127.7, 127.4, 126.8, 126.2, 120.5, 119.4, 30.9, 28.2; LRMS (EI) m/z: 403 (M+); HRMS (EI-TOF) Calcd. For C23H1879BrNO: 403.0572, found: 403.0550; IR (neat): 3074, 1718, 1636, 1488, 1365, 1301, 1235, 1166, 1067, 1012 cm−1.
5-(Diphenylmethylene)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (3o). Obtained as yellow crystals in 69% (54.4 mg, 3o:2o = 95:5), recrystallized from DCM/hexane, mp. 169–170 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.32 (2H, t, J = 7.6 Hz), 7.26–7.18 (5H, m), 7.10 (2H, d, J = 8.3 Hz), 6.84–6.83 (3H, m), 6.69 (2H, dd, J = 7.6, 1.4 Hz), 3.01 (2H, t, J = 7.7 Hz), 2.72 (2H, t, J = 7.7 Hz); 13C{1H, 19F} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.0, 141.5, 139.1, 139.0, 137.2, 130.0, 129.9, 128.2, 127.8, 127.4, 126.9, 126.4, 126.3, 125.0, 123.7, 121.0, 31.0, 28.2; 19F NMR (565 MHz, CDCl3) δ (ppm): −62.1; LRMS (EI) m/z: 393 (M+); HRMS (EI-TOF) Calcd. For C24H18F3NO: 393.1340, found: 393.1328; IR (neat): 3060, 1721, 1636, 1592, 1490, 1366, 1324, 1232, 1161, 851, 753 cm−1.
4-(2-(Diphenylmethylene)-5-oxopyrrolidin-1-yl)benzonitrile (3p). Obtained as colorless crystals in 84% (59.1 mg, 3p:2p = 98:2), recrystallized from DCM/hexane, mp. 200–201 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.32 (2H, t, J = 7.5 Hz), 7.28–7.25 (3H, m), 7.18 (2H, d, J = 6.9 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.90–6.86 (3H, m), 6.72–6.71 (2H, m), 3.01 (2H, t, J = 7.7 Hz), 2.73 (2H, t, J = 7.7 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 175.8, 141.2, 140.0, 139.0, 136.73, 136.72, 131.8, 129.9, 128.3, 127.6, 127.1, 126.7, 126.2, 121.8, 118.5, 108.9, 31.2, 28.3; LRMS (EI) m/z: 350 (M+); HRMS (EI-TOF) Calcd. For C24H18N2O: 350.1419, found: 350.1396; IR (neat): 3044, 2224, 1721, 1635, 1601, 1506, 1355, 1227, 1162, 844 cm−1.
Methyl 4-(2-(diphenylmethylene)-5-oxopyrrolidin-1-yl)benzoate (3q). Obtained as colorless crystals in 84% (64.4 mg, 3q:2q = 98:2), recrystallized from DCM/hexane, mp. 191–192 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.65 (2H, d, J = 8.9 Hz), 7.31 (2H, t, J = 7.6 Hz), 7.26–7.24 (1H, m), 7.19 (2H, d, J = 6.8 Hz), 7.09 (2H, d, J = 8.2 Hz), 6.85–6.81 (3H, m), 6.73 (2H, d, J = 7.6 Hz), 3.84 (3H, s), 3.00 (2H, t, J = 7.9 Hz), 2.71 (2H, t, J = 7.9 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.0, 166.4, 141.6, 140.2, 139.0, 137.3, 130.0, 129.3, 128.2, 127.4, 127.1, 126.9, 126.40, 126.39, 125.6, 121.4, 52.0, 31.2, 28.4; LRMS (EI) m/z: 383 (M+); HRMS (EI-TOF) Calcd. For C25H21NO3: 383.1521, found: 383.1511; IR (neat): 3056, 2952, 1723, 1710, 1630, 1439, 1361, 1278, 1227, 855, 765 cm−1.
1-(3-Bromophenyl)-5-(diphenylmethylene)pyrrolidin-2-one (3r). Obtained as yellow crystals in 78% (63.2 mg, 3r:2r = 95:5), recrystallized from DCM/hexane, mp. 138–140 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.31 (2H, t, J = 7.5 Hz), 7.25–7.23 (1H, m), 7.18 (2H, d, J = 7.5 Hz), 7.06 (1H, s), 7.01 (2H, d, J = 8.0 Hz), 6.92–6.85 (4H, m), 6.74 (2H, d, J = 6.5 Hz), 2.99 (2H, t, J = 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 176.0, 141.6, 139.0, 137.4, 137.1, 129.93, 129.91, 129.4, 129.1, 129.0, 128.2, 127.4, 126.8, 126.3, 124.9, 121.4, 120.8, 30.9, 28.2; LRMS (EI) m/z: 403 (M+); HRMS (EI-TOF) Calcd. For C23H1879BrNO: 403.0572, found: 403.0580; IR (neat): 3057, 1724, 1631, 1590, 1571, 1476, 1352, 1220, 1155, 764 cm−1.
1-(Benzo[d]thiazol-2-yl)-5-(diphenylmethylene)pyrrolidin-2-one (3s). Obtained as colorless needles in 38% (29.9 mg), recrystallized from DCM/hexane, mp. 192–193 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.64 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.34–7.23 (6H, m), 7.19 (1H, t, J = 7.2 Hz), 6.93 (2H, d, J = 7.6 Hz), 6.82 (2H, t, J = 7.9 Hz), 6.64 (1H, t, J = 7.5 Hz), 3.08 (2H, t, J = 7.5 Hz), 2.79 (2H, t, J = 7.5 Hz); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 175.1, 154.2, 148.3, 140.9, 140.3, 134.8, 133.1, 130.2, 129.0, 128.1, 127.3, 127.2, 126.4, 125.7, 125.5, 124.3, 122.1, 120.8, 31.5, 28.5; LRMS (EI) m/z: 382 (M+); HRMS (EI-TOF) Calcd. for C24H18N2OS (M+): 382.1140, found: 382.1167; IR (neat): 3048, 2914, 1723, 1635, 1512, 1279, 1234, 1168, 749 cm−1.
5-(Chlorodiphenylmethyl)-1-phenylpyrrolidin-2-one (4a). Obtained as colorless needles in 50% (36.2 mg), recrystallized from DCM/hexane, mp. 156–157 °C. 1H NMR (600 MHz, CDCl3/TMS) δ (ppm): 7.43 (2H, d, J = 6.9 Hz), 7.31–7.23 (5H, m), 7.09 (4H, d, J = 4.8 Hz), 7.05–7.01 (3H, m), 7.00–6.96 (1H, m), 5.62 (1H, d, J = 8.3 Hz), 2.62–2.54 (1H, m), 2.34–2.28 (2H, m), 2.24–2.15 (1H, m); 13C{1H} NMR (150 MHz, CDCl3/TMS) δ (ppm): 175.9, 142.6, 141.2, 138.7, 128.3, 128.2, 128.1, 127.9, 127.8, 127.5, 125.8, 125.77, 125.76, 82.5, 67.5, 30.5, 24.2; LRMS (FAB) m/z: 362 (M+H)+; HRMS (FAB-EB) Calcd. For C23H2135ClNO (M+H)+: 362.1312, found: 362.1324; IR (neat): 3067, 1689, 1599, 1499, 1404, 1291, 1039, 749 cm−1.

4. Conclusions

In conclusion, we developed a novel copper-catalyzed intramolecular olefinic C(sp2)–H amidation of 4-pentenamides. This reaction is an efficient approach to synthesize α,β-unsaturated-γ-alkylidene-γ-lactams or the α,β-saturated derivatives, which were controllable by varying the reaction conditions. The reaction exhibits good tolerance to various functional groups including alkyl, methoxy, halogen (fluoride, chloride, and bromide), trifluoromethyl, ester, and cyano moieties. Further studies aimed at expanding the substrate scope and elucidating the reaction mechanism are currently underway.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28186682/s1, Table S1: Effect of reaction parameter for the synthesis of 2a; Table S2: Copper optimization for the synthesis of 3a; Table S3: Optimization of copper and silver salts for the synthesis of 3a; Table S4: Detailed reaction conditions for the synthesis of 3a; Table S5: Crystal data and structure refinements for 4a; Scheme S1: Unsuccessful substrates under condition B; Figure S1: ORTEP diagram of 4a with thermal ellipsoids drawn at 50% probability level (CCDC No. 2284469). References [53,54,55] are cited in the supplementary materials.

Author Contributions

Conceptualization, K.N.-K., M.H. and Y.K.; methodology, K.N.-K., M.H. and Y.K.; formal analysis, K.N.-K. and M.H.; investigation, K.N.-K., M.H. and E.K.; data curation, K.N.-K., M.H. and E.K.; discussion on mechanism, K.N.-K., M.H., M.S. and A.Y.; writing—original draft preparation, K.N.-K., M.H. and Y.K.; writing—review and editing, all authors; supervision, K.N.-K. and Y.K.; project administration, K.N.-K. and Y.K.; funding acquisition, K.N.-K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (Grant no. 21K06470 to K.N.K.) and Transformative Research Areas (A) Digi-TOS (Grant no. 21H05224 to A.Y.). This work was also supported by Takeda Science Foundation, the Iwatani Naoji Foundation, Astellas Foundation for Research on Metabolic Disorders, SEI Group CSR Foundation, the Uehara Memorial Foundation to K.N.K. and JST, the establishment of university fellowships towards the creation of science technology innovation (Grant no. JPMJFS2102 to M.H.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The Supplementary Materials are available free of charge on the website.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Molecules 28 06682 sch001
Scheme 1. Syntheses of γ-alkylidene-γ-lactams [39].
Scheme 1. Syntheses of γ-alkylidene-γ-lactams [39].
Molecules 28 06682 sch001
Molecules 28 06682 sch002
Scheme 2. Substrate scope of 5-alkylidene-3-pyrrolin-2-one synthesis. a Isolated yields. Reaction conditions: 1 (0.20 mmol), CuF2 (0.020 mmol), 4-tert-butylpyridine (0.20 mmol), and tBuOOtBu (0.80 mmol) in 1,2-DCE (2.5 mL) at 120 °C for 18 h. b Concentration of 1 was 0.10 M. c 5.0 equiv of tBuOOtBu was used. d 75 mol% of 4-tert-butylpyridine was used. e 3.0 equiv of tBuOOtBu was used. f Concentration of 1 was 0.13 M. g Reaction was conducted at 140 °C. h Concentration of 1 was 0.067 M. i Reaction conditions: 1 (0.20 mmol), CuF2 (0.020 mmol), 4-tert-butylpyridine (0.30 mmol), and tBuOOtBu (1.0 mmol) in 1,2-DCE (1.0 mL) at 140 °C for 26 h.
Scheme 2. Substrate scope of 5-alkylidene-3-pyrrolin-2-one synthesis. a Isolated yields. Reaction conditions: 1 (0.20 mmol), CuF2 (0.020 mmol), 4-tert-butylpyridine (0.20 mmol), and tBuOOtBu (0.80 mmol) in 1,2-DCE (2.5 mL) at 120 °C for 18 h. b Concentration of 1 was 0.10 M. c 5.0 equiv of tBuOOtBu was used. d 75 mol% of 4-tert-butylpyridine was used. e 3.0 equiv of tBuOOtBu was used. f Concentration of 1 was 0.13 M. g Reaction was conducted at 140 °C. h Concentration of 1 was 0.067 M. i Reaction conditions: 1 (0.20 mmol), CuF2 (0.020 mmol), 4-tert-butylpyridine (0.30 mmol), and tBuOOtBu (1.0 mmol) in 1,2-DCE (1.0 mL) at 140 °C for 26 h.
Molecules 28 06682 sch002
Molecules 28 06682 sch003
Scheme 3. Substrate scope of 5-alkylidene-pyrrolidin-2-one synthesis. Isolated yields. Ratio was determined by 1H-NMR analysis. a Reaction conditions: 1 (0.20 mmol), CuBr (0.020 mmol), AgBF4 (0.020 mmol), 4-tert-butylpyridine (0.050 mmol), and MnO2 (0.60 mmol) in 1,2-DCE (1.5 mL) at 120 °C for 24 h. b Reaction was conducted at 140 °C.
Scheme 3. Substrate scope of 5-alkylidene-pyrrolidin-2-one synthesis. Isolated yields. Ratio was determined by 1H-NMR analysis. a Reaction conditions: 1 (0.20 mmol), CuBr (0.020 mmol), AgBF4 (0.020 mmol), 4-tert-butylpyridine (0.050 mmol), and MnO2 (0.60 mmol) in 1,2-DCE (1.5 mL) at 120 °C for 24 h. b Reaction was conducted at 140 °C.
Molecules 28 06682 sch003
Molecules 28 06682 sch004
Scheme 4. Control experiments.
Scheme 4. Control experiments.
Molecules 28 06682 sch004
Molecules 28 06682 sch005
Scheme 5. Plausible mechanism for copper-catalyzed intramolecular dehydrogenative coupling of 1a.
Scheme 5. Plausible mechanism for copper-catalyzed intramolecular dehydrogenative coupling of 1a.
Molecules 28 06682 sch005
Table 1. Effect of reaction parameters a.
Table 1. Effect of reaction parameters a.
Molecules 28 06682 i001
EntryVariation from Standard ConditionsYield (%) b
1None76 (85)
2CuCl, CuCl2, or Cu(OAc)2 instead of CuF239–75
3Pyridine, DMAP, or 1,10-phen instead of 4-tert-butylpyridine21–66
4W/O 4-tert-butylpyridine29
5tBuOOH, tBuOOAc, or PIDA instead of tBuOOtBu0–35
6MnO2 instead of tBuOOtBu5 c
7DCM, toluene, or PhCF3 instead of 1,2-DCE0–44
8At 100 °C73
91.0 mmol Scale83 (87)
a Reaction conditions: 1a (0.20 mmol), 4-tert-butylpyridine (0.20 mmol), tBuOOtBu (0.80 mmol), 1,2-DCE (2.5 mL), at 120 °C for 18 h under Ar. b Determined by 1H-NMR using 1,1,2-trichloroethane as the internal standard. Isolated yield in parentheses. c 5-(Diphenylmethylene)-1-phenylpyrrolidin-2-one 3a was obtained in 89% yield instead of 2a.
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Nozawa-Kumada, K.; Hayashi, M.; Kwon, E.; Shigeno, M.; Yada, A.; Kondo, Y. Copper-Catalyzed Intramolecular Olefinic C(sp2)–H Amidation for the Synthesis of γ-Alkylidene-γ-lactams. Molecules 2023, 28, 6682. https://doi.org/10.3390/molecules28186682

AMA Style

Nozawa-Kumada K, Hayashi M, Kwon E, Shigeno M, Yada A, Kondo Y. Copper-Catalyzed Intramolecular Olefinic C(sp2)–H Amidation for the Synthesis of γ-Alkylidene-γ-lactams. Molecules. 2023; 28(18):6682. https://doi.org/10.3390/molecules28186682

Chicago/Turabian Style

Nozawa-Kumada, Kanako, Masahito Hayashi, Eunsang Kwon, Masanori Shigeno, Akira Yada, and Yoshinori Kondo. 2023. "Copper-Catalyzed Intramolecular Olefinic C(sp2)–H Amidation for the Synthesis of γ-Alkylidene-γ-lactams" Molecules 28, no. 18: 6682. https://doi.org/10.3390/molecules28186682

APA Style

Nozawa-Kumada, K., Hayashi, M., Kwon, E., Shigeno, M., Yada, A., & Kondo, Y. (2023). Copper-Catalyzed Intramolecular Olefinic C(sp2)–H Amidation for the Synthesis of γ-Alkylidene-γ-lactams. Molecules, 28(18), 6682. https://doi.org/10.3390/molecules28186682

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