Copper-Mediated Decarboxylative Coupling of 3-Indoleacetic Acids with Pyrazolones.

A copper-mediated decarboxylative coupling reaction of 3-indoleacetic acids with pyrazolones was described. This protocol realized new functionalization of pyrazolones under simple reaction conditions and exhibited high functional group compatibility and broad substrate scope. Notably, the products displayed antiproliferative activity against cancer cells.

Introduction

Pyrazolones are very important five-membered N-heterocycles that have a broad spectrum of biological activities containing analgesic, anti-inflammatory, antibacterial, antitumor, and antiviral activities (Scheme ).[1] Among them, antipyrine (2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) and its derivatives are well-known nonsteroidal anti-inflammatory drugs (NSAIDs), which have been widely used in clinical medicines for a long time.[2] The great medicinal significance of pyrazolones prompted chemists to synthesize new pyrazolones with different functional groups. In the past few decades, the direct C–H functionalization reactions featured with atom- and step-economy have become important tools for modifying organic compounds.[3] Until now, there were some examples about direct C–H functionalization of pyrazolones including arylation,[4] alkenylation,[5] alkynylation,[6] acylation,[7] and thiolation.[8] However, these methods had some disadvantages, such as using precious metals or unavailable starting materials, utilizing strong oxidant, and needing complex reaction conditions. Therefore, it is desired and meaningful to explore new methods for functionalizations of this bioactive skeleton.

Scheme 1

Some Marketed Drugs Based on Pyrazolones

Carboxylic acids are one of the most abundant feedstocks featured with inexpensive prices, great structural diversities, and easy operations.[9] Thus, utilizing carboxylic acids to realize functionalization reactions is a good synthesis strategy. In recent decades, various types of carboxylic acids have been extensively investigated for functionalization reactions. For example, α-keto acids were used as common acylation reagents.[10] Gooßen and other groups reported metal-catalyzed decarboxylative arylation reactions with electron-poor benzoic acids.[11] Alkynyl and alkenyl carboxylic acids were widely reported as alkynyl and alkenyl sources.[12,13] Li and co-workers achieved construction of C(sp3)–halo, C(sp3)–C, and C(sp3)–N bonds with aliphatic carboxylic acids.[14]

It was rare to realize functionalization of pyrazolones via decarboxylative process. Yotphan’s group has reported a decarboxylative C–H acylation of pyrazolones with α-keto acids using K2S2O8 as oxidant (Scheme a).[7a] However, the more challenging C(sp3)-carboxylic acids have not been used to functionalize pyrazolones. In our previous studies, we have developed several decarboxylative coupling reactions with 3-indoleacetic acids in the presence of copper salts.[15] In addition, we found that the decarboxylative transformation involving 3-indoleacetic acids can occur without bases, ligands, and other additives. Indole is a common framework in drug molecules that exhibits a variety of biological activities,[16] so we preliminarily evaluated the bioactivities of the products. To our delight, the products exhibited a broad spectrum of anticancer activities against the cancer cell lines in vitro. Based on our above studies, we supposed to realize direct C–H functionalization of pyrazolones with the decarboxylative reaction of 3-indoleacetic acids. The new products consisted of pyrazolones and indole ring connected by a methylene unit, which may have good biological activities. Herein, we presented a new method for direct C–H functionalization of pyrazolones via copper-mediated decarboxylative reaction with 3-indoleacetic acids under simple and mild reaction conditions (Scheme b). To the best of our knowledge, this is the first example about direct functionalization of pyrazolones with C(sp3)-carboxylic acids.

Scheme 2

Decarboxylative Functionalizations of Pyrazolones with Carboxylic Acids

Results and Discussion

The study started by optimizing the conditions for the model reaction of antipyrine 1a with 3-indoleacetic acid 2a (Table ). First, the reaction using Cu(OTf)2 (2 equiv) as oxidant was conducted in DMF at 90 °C under N2 atmosphere for 12 h, which afforded the desired product 3aa in 39% yield (entry 1). Whereafter, a series of copper salts such as CuO, CuCl2, CuI, CuBr2, Cu(OAc)2·H2O, and CuSO4 were screened (entries 2–7). To our delight, the yield of 3aa rose sharply to 88% in the presence of Cu(OAc)2·H2O. We tried to perform the reaction with catalytic amounts of copper salts and oxidants including Ag2CO3, K2S2O8, PhI(OAc)2, TBHP, O2 and H2O2, but the yields of the product 3aa were sharply decreased (entries 8–13). Next, various solvents (dioxane, toluene, DMA, DMSO, NMP, DCE) were screened for this transformation, and the results showed that DMF was the best choice (entries 14–19). When we performed the reaction at a lower temperature of 80 °C, it showed lower reactivity (entry 20). Hence, the optimal conditions are as follows: 1a (0.4 mmol), 2a (0.3 mmol), Cu(OAc)2·H2O (0.6 mmol) in DMF (1.5 mL) at 90 °C for 12 h under N2 atmosphere.

Table 1

Optimization of the Reaction Conditionsa

entry	oxidant	solvent	yield (%)
1	Cu(OTf)2	DMF	39
2	CuO	DMF	<10
3	CuCl2	DMF	n.d.
4	CuI	DMF	28
5	CuBr2	DMF	n.d.
6	Cu(OAc)2·H2O	DMF	88
7	CuSO4	DMF	23
8b	Ag2CO3	DMF	28
9b	K2S2O8	DMF	18
10b	PhI(OAc)2	DMF	24
11b	TBHP	DMF	34
12b	O2	DMF	25
13b	H2O2	DMF	<10
14	Cu(OAc)2·H2O	dioxane	78
15	Cu(OAc)2·H2O	toluene	57
16	Cu(OAc)2·H2O	DMA	58
17	Cu(OAc)2·H2O	DMSO	74
18	Cu(OAc)2·H2O	NMP	45
19	Cu(OAc)2·H2O	DCE	59
20 c	Cu(OAc)2·H2O	DMF	76

Unless otherwise stated, the reaction was performed with 1a (0.4 mmol), 2a (0.3 mmol), oxidant (2 equiv), in solvent (1.5 mL) at 90 °C for 12 h under N2 atmosphere.

10 mol % Cu(OAc)2·H2O was added as catalyst.

Yield was with respect to the temperature at 80 °C.

With the optimal conditions in hand, the substrate scope exploration was then started from a variety of substituted 3-indoleacetic acids, as shown in Scheme . Methyl group at the 2-position of 3-indoleacetic acid did not affect the reaction and provided the corresponding product 3ab in 74% yield. When 4-chloroindole-3-acetic acid and 4-bromoindole-3-acetic acid were used, the desired products were afforded in 96 and 95% yields, respectively (3ac, 3ad). The compatibility of halogen groups made the further modifications of the products possible. Different substituents, including electron-donating substituents (CH3, OCH3, OBn), weak electron-withdrawing substituents (F, Cl, Br), and strong electron-withdrawing substituent (NO2) at the 5th-position of 3-indoleacetic acids were compatible, gave the products 3ae–3ak in 65–97% yields. Among them, the substrates with electron-withdrawing substituents had better yields. Meanwhile, 6-chloro substrate was well tolerated as the yield of the corresponding product 3al was excellent.

Scheme 3

Substrate Scope of 3-Indoleacetic Acids

Reaction conditions: 1a (0.4 mmol), 2 (0.3 mmol), Cu(OAc)2·H2O (2 equiv), in DMF (1.5 mL) at 90 °C for 12 h under N2 atmosphere. Isolated yield.

Subsequently, we investigated the scope of pyrazolones and the results were summarized in Scheme . First, 1-phenyl pyrazolones with various substituents (CH3, OCH3, F, Cl, Br, CN, SO2Me) at the para position of the phenyl ring proceeded smoothly with 3-indoleacetic acid 2a to afford the corresponding products in moderate to good yields (3ba–3ha). The structure of 3ca was confirmed by X-ray diffraction analysis (CCDC 2105311). Among them, for the substrates with electron-donating groups, higher yields were obtained. Furthermore, 1-phenyl pyrazolones with methyl at the ortho, meta, or para–meta position of the phenyl ring were tolerable, and the expected products 3ia, 3ja, and 3ka were obtained in 70, 93, and 84% yields, respectively. Besides phenyl group, other aromatic rings such as the naphthyl ring was compatible to give 3la in 87% yield. Moreover, 1-alkyl pyrazolones such as methyl, isopropyl, and cyclohexyl also exhibited good reactivity, and satisfactory yields of products were obtained. (3m–3o). To our delight, different alkyl or aryl groups on the N2 or C3 position of pyrazolones were applicable, providing the target products in moderate to good yields (3pa–3va).

Scheme 4

Substrate Scope of Pyrazolones

Reaction conditions: 1 (0.4 mmol), 2a (0.3 mmol), Cu(OAc)2·H2O (2 equiv), in DMF (1.5 mL) at 90 °C for 12 h under N2 atmosphere. Isolated yield.

To gain more insight into the mechanism, we conducted some control experiments. The reaction was not inhibited with radical scavengers TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,6-di-tert-butyl-4-methyl phenol) (Scheme , eqs 1 and 2). These results revealed the transformation may not involve a radical pathway. Based on the control experiments and previous literatures,[7,15] a possible mechanism was proposed (Scheme ). First, 3-indoleacetic acid 1a reacts with copper salts to produce copper-carboxylate intermediate A.[15] Subsequently, organic copper intermediate B forms from intermediate A via decarboxylation.[15] The reaction of intermediate B with phenazone 2a provides intermediate C.[7] Finally, the reductive elimination of intermediate C occurs to give the product 3aa.[7,15a]

Scheme 5

Control Experiments and Plausible Reaction Pathway

Next, we evaluated the antiproliferative activity of newly formed products against different cancer cell lines including human colon cancer cells (HCT116) and mouse melanoma cells (B16-F10) by using a MTT assay with 5-fluorouracil (5-Fu) as a positive control (Table ). To our delight, some products exhibited antiproliferative activity against tested cell lines. In particular, compound 3ta exhibited potent inhibitory activity against HCT116 cell lines with IC50 values of 19.35 μM, and 3la inhibited the B16–10 cell viability with an IC50 of 16.39 μM. In order to exclude the residual copper affecting the activity of these compounds, we measured the content of copper in products 3la and 3ta using atomic absorption spectrometry. The concentrations of copper were both below the detection limit (<0.05 mg/L). By calculation, the concentrations of copper in products 3la and 3ta were both less than 0.01 mg/g.

Table 2

Biological Applications

	IC50(uM)
compounds	HCT116	B16-F10
3ha	>100	31.81 ± 6.28
3ia	67.70 ± 12.93	39.75 ± 9.91
3ka	97.81 ± 15.38	43.63 ± 23.31
3la	95.61 ± 20.18	16.39 ± 5.66
3qa	>100	59.84 ± 18.30
3sa	44.35 ± 14.34	>100
3ta	19.35 ± 2.34	>100
3ua	22.02 ± 5.98	85.85 ± 12.62
5-Fu	86.15 ± 23.61	104.10 ± 21.37

In conclusion, we have developed a copper-mediated decarboxylative coupling reaction, which realized new functionalization of pyrazolones with 3-indoleacetic acids. This decarboxylative reaction occurred at a relatively low temperature, and without bases or ligands. The new products were obtained in moderate to good yields with good functional group tolerance. We found the products had antiproliferative activity against cancer cells through the preliminary bioactivity evaluation. Further efforts to expand decarboxylative coupling reactions with 3-indoleacetic acids are now underway in our laboratory.

Experimental Section

General Information

1H and 13C{1H} NMR spectra were recorded on a Bruker 400 MHz NMR spectrometer with CDCl3 as the solvent and TMS as the internal standard. IR spectra were recorded on a Thermo fisher Nicolet 6700 spectrometer. HRMS spectra were obtained using the Agilent 6210 ESI/TOF mass spectrometer. Determination of copper content was performed using atomic absorption spectroscopy (Agilent 240FS AA). TLC was performed using commercially available 100–400 mesh silica gel plates (GF254), and visualization was effected at 254 nm. Column chromatography was carried out on silica gel (200–300 mesh). All commercially available reagents were used as received. Pyrazolone 1b–1v were synthesized by literature procedures.[5b,7a,8b]

General Procedure for Products 3

A Schlenk tube (25 mL) equipped with a magnetic stirrer bar was charged with pyrazolones 1 (0.4 mmol), 3-indoleacetic acids 2 (0.3 mmol), Cu(OAc)2·H2O (0.6 mmol), and DMF (1.5 mL) and stirred together at 90 °C (oil bath temperature) for 12 h under N2 atmosphere. After the reaction was completed, the mixture was washed with saturated NaHCO3 and extracted with EtOAc. The combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to afford the pure product 3.

Gram-Scale Synthesis of 3aa

A Schlenk tube (100 mL) equipped with a magnetic stirrer bar was charged with antipyrine 1a (6.67 mmol, 1.254 g), 3-indoleacetic acids 2a (5.0 mmol, 0.875 g), Cu(OAc)2·H2O (10 mmol, 2.0 g), and DMF (20 mL) and stirred together at 90 °C (oil bath temperature) for 12 h under N2 atmosphere. After the reaction was completed, the mixture was washed with saturated NaHCO3 (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 1:2) on silica gel to obtain product 3aa (1.189 g, 75%).

Cell Culture and Evaluation of the Antiproliferative Activity

The compounds were evaluated for their in vitro antiproliferative activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cancer cell lines HCT116 and B16-F10 were cultured under standard culture conditions at 37 °C and 5% CO2 atmosphere in DMEM medium supplemented with 10% fetal bovine serum, 1% penicillin–streptomycin. Cells were plated at a density of 5000 cells/well in 96-well plates. On the following day, the cells were incubated with tested compounds for at least three cell doublings and incubated at 37 °C for another 48 h, with 5-Fluorouracil (FU) as the positive control. At the indicated time, the culture medium was replaced with 100 μL medium containing 10% MTT solution (5 mg/mL in PBS), and the cells were incubated at 37 °C for another 4 h. The absorbance at 570 nm was measured using a microplate reader. The IC50 values were calculated by nonlinear regression analysis using GraphPad Prism 8.0.

4-((1H-Indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3aa)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (83.8 mg, 88%); m.p. = 161–162 °C. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.65 (s, 1H), 7.38 (s, 4H), 7.21–7.18 (m, 2H), 7.04 (s, 2H), 6.86 (s, 1H), 3.73 (s, 2H), 2.89 (s, 3H), 2.07 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 153.3, 136.4, 135.2, 129.0, 127.0, 126.1, 123.7, 122.6, 121.3, 118.7, 118.6, 113.4, 111.3, 109.9, 35.9, 18.1, 11.1. IR (KBr): 3248. 2922, 1643, 1496, 1431, 1341, 1148, 743 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H20N3O 318.1601; Found 318.1601.

1,5-Dimethyl-4-((2-methyl-1H-indol-3-yl)methyl)-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ab)

Eluent: petroleum ether/ethyl acetate (1:2). Brown solid (73.6 mg, 74%); m.p. = 90–92 °C. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.61 (s, 1H), 7.44 (s, 4H), 7.27–7.22 (m, 2H), 7.09–7.06 (m, 2H), 3.74 (s, 2H), 2.94 (s, 3H), 2.44 (s, 3H), 2.09 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 153.2, 135.3, 135.2, 131.8, 128.9, 128.4, 126.0, 123.6, 120.3, 118.7, 118.0, 110.3, 110.1, 108.8, 35.9, 17.2, 11.7, 11.0. IR (KBr): 3421, 2921, 1646, 1496, 1311, 1137, 744, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O 332.175; Found 332.1759.

4-((4-Chloro-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ac)

Eluent: petroleum ether/ethyl acetate (1:1). Orange solid (101.3 mg, 96%); m.p. = 242–244 °C. 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 7.45–7.42 (m, 4H), 7.28–7.26 (m, 1H), 7.10–7.05 (m, 1H), 6.94–6.92 (m, 2H), 6.85 (s, 1H), 4.08 (s, 2H), 3.01 (s, 3H), 2.15 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 153.7, 138.0, 135.3, 129.1, 126.4, 125.8, 124.4, 123.9, 123.8, 121.7, 119.8, 113.3, 110.3, 110.0, 36.1, 19.7, 11.3. IR (KBr): 3205, 2921, 1641, 1495, 1341, 1185, 756, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19ClN3O 352.1211; Found 352.1212.

4-((4-Bromo-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ad)

Eluent: petroleum ether/ethyl acetate (1:1). Pink solid (112.9 mg, 95%); m.p. = 237–238 °C. 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 7.45–7.39 (m, 4H), 7.28–7.26 (m, 1H), 7.14 (d, J = 7.7 Hz, 2H), 6.85 (t, J = 7.8 Hz, 1H), 6.79 (s, 1H), 4.11 (s, 2H), 3.02 (s, 3H), 2.12 (s, 3H). 113C{1H} NMR (100 MHz, Methanol-d4) δ 167.2, 154.7, 139.9, 135.9, 130.5, 129.0, 126.8, 126.5, 125.3, 124.1, 123.3, 114.8, 114.8, 111.9, 108.5, 35.6, 20.8, 11.1. IR (KBr): 3202, 2921, 2641, 1495, 1334, 1182, 756, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19BrN3O 396.0706; Found 396.0705.

1,5-Dimethyl-4-((5-methyl-1H-indol-3-yl)methyl)-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ae)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (64.6 mg, 65%); m.p. = 181–183 °C. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.42–7.41 (m, 5H), 7.24–7.22 (m, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.95 (s, 2H), 3.73 (s, 2H), 2.95 (s, 3H), 2.43 (s, 3H), 2.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 153.3, 135.4, 134.7, 129.0, 127.9, 127.3, 126.0, 123.6, 123.0, 122.7, 118.3, 113.1, 110.9, 110.2, 36.1, 21.5, 18.1, 11.2. IR (KBr): 3256, 2920, 1642, 1495, 1311, 1136, 759, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O 332.1757; Found 332.1758.

4-((5-Methoxy-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3af)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (68.7 mg, 66%); m.p. = 154–156 °C. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.45–7.44 (m, 4H), 7.28 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 6.79 (d, J = 6.7 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 2H), 2.98 (s, 3H), 2.15 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 153.6, 153.4, 135.4, 131.6, 129.0, 127.4, 126.1, 123.6, 123.2, 113.5, 111.9, 111.7, 110.0, 100.7, 55.8, 36.1, 18.2, 11.1. IR (KBr): 3255, 2923, 1642, 1486, 1311, 1061, 734, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O2 348.1707; Found 348.1706.

4-((5-(Benzyloxy)-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ag)

Eluent: petroleum ether/ethyl acetate (1:1). Red solid (88.9 mg, 70%); m.p. = 147–148 °C. 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.43–7.38 (m, 5H), 7.33–7.27 (m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.04 (s, 2H), 3.68 (s, 2H), 2.89 (s, 3H), 2.03 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 153.3, 152.7, 137.9, 135.3, 131.8, 129.0, 128.3, 127.5, 127.3, 126.1, 123.6, 123.4, 113.3, 112.3, 112.0, 110.0, 102.2, 70.8, 36.0, 18.2, 11.1. IR (KBr): 3254, 2904, 1646, 1496, 1202, 1023, 736, 696 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C27H26N3O2 424.2020; Found 424.2019.

4-((5-Fluoro-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ah)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (84.5 mg, 84%); m.p. = 128–130 °C. 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.36 (s, 4H), 7.21 (d, J = 8.0 Hz, 2H), 6.97–6.95 (m, 1H), 6.80 (s, 1H), 6.75–6.70 (m, 1H), 3.64 (s, 2H), 2.92 (s, 3H), 2.08 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 157.3 (d, J = 232.0 Hz), 153.1, 135.0, 133.0, 129.0, 127.1 (d, J = 10 Hz), 126.4, 124.6, 123.9, 113.1 (d, J = 7 Hz), 112.0 (d, J = 10.0 Hz), 109.3 (d, J = 26 Hz), 109.2, 103.2 (d, J = 23 Hz), 35.8, 18.1, 11.0. IR (KBr): 3232, 2920, 1642, 1487, 1312, 1168, 936, 696 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19FN3O 336.1507; Found 336.1506.

4-((5-Chloro-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ai)

Eluent: petroleum ether/ethyl acetate (1:2). Pink solid (102.4 mg, 97%); m.p. = 148–149 °C. 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 7.49 (s, 1H), 7.40–7.38 (m, 4H), 7.24 (s, 1H), 6.97–6.92 (m, 2H), 6.77 (s, 1H), 3.64 (s, 2H), 2.96 (s, 3H), 2.13 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 153.0, 135.0, 134.8, 129.0, 128.0, 126.5, 124.3, 124.2, 124.0, 121.2, 117.7, 112.6, 112.5, 109.2, 35.8, 18.1, 11.1. IR (KBr): 3223, 2922, 1642, 1455, 1312, 1102, 890, 736 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19ClN3O 352.1211; Found 352.1211.

4-((5-Bromo-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3aj)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (102.2 mg, 86%); m.p. = 164–165 °C. 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 7.64 (s, 1H), 7.41–7.39 (m, 4H), 7.25 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 3.65 (s, 2H), 2.98 (s, 3H), 2.15 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 153.1, 135.1, 135.1, 129.1, 128.7, 126.5, 124.2, 124.0, 123.8, 120.8, 113.0, 112.6, 111.9, 109.4, 36.0, 18.2, 11.2. IR (KBr): 3242, 2922, 1644, 1496, 1326, 881, 736, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19BrN3O 396.0706; Found 396.0706.

1,5-Dimethyl-4-((5-nitro-1H-indol-3-yl)methyl)-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ak)

Eluent: petroleum ether/ethyl acetate (1:2). Yellow solid (89.1 mg, 82%); m.p. = 191–192 °C. 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.37 (s, 4H), 7.25 (s, 1H), 6.74 (d, J = 15.1 Hz, 2H), 3.67 (s, 2H), 3.04 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 152.8, 140.6, 139.6, 134.7, 129.2, 127.0, 126.2, 126.0, 124.4, 116.5, 115.5, 115.0, 111.2, 108.4, 35.8, 18.5, 11.2. IR (KBr): 3178, 1638, 1519, 1330, 1098, 754, 737, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19N4O3 363.1452; Found 363.1447.

4-((6-Chloro-1H-indol-3-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3al)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (101.3 mg, 96%); m.p. = 142–143 °C. 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.50 (s, 1H), 7.48–7.39 (m, 4H), 7.26 (s, 1H), 7.08 (s, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.81 (s, 1H), 3.68 (s, 2H), 2.97 (s, 3H), 2.13 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 153.1, 136.8, 135.0, 129.1, 127.0, 126.5, 125.5, 124.0, 123.3, 119.4, 119.3, 113.3, 111.2, 109.4, 35.8, 18.1, 11.1. IR (KBr): 3244, 2924, 1636, 1496, 1456, 1338, 907, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19ClN3O 352.1211; Found 352.1211.

4-((1H-Indol-3-yl)methyl)-1,5-dimethyl-2-(p-tolyl)-1,2-dihydro-3H-pyrazol-3-one (3ba)

Eluent: petroleum ether/ethyl acetate (1:1). Pink solid (89.5 mg, 90%); m.p. = 182–183 °C. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.65 (s, 1H), 7.25–7.14 (m, 5H), 7.03 (s, 2H), 6.87 (s, 1H), 3.73 (s, 2H), 2.88 (s, 3H), 2.33 (s, 3H), 2.06 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 152.7, 136.4, 136.2, 132.7, 129.6, 127.0, 124.0, 122.7, 121.2, 118.6, 113.4, 111.3, 109.7, 35.7, 20.9, 18.1, 11.0. IR (KBr): 3420, 2921, 1646, 1508, 1456, 1339, 1149, 742 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O 332.1757; Found 332.1757.

4-((1H-Indol-3-yl)methyl)-2-(4-methoxyphenyl)-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3ca)

Eluent: petroleum ether/ethyl acetate (1:1). Orange solid (95.9 mg, 92%); m.p. = 182–183 °C. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.09–7.04 (m, 2H), 6.93–6.90 (m, 3H), 3.78 (s, 3H), 3.74 (s, 2H), 2.90 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 158.3, 152.0, 136.4, 128.1, 127.1, 126.1, 122.7, 121.3, 118.7, 114.3, 113.7, 111.3, 109.4, 55.5, 35.5, 18.1, 11.1. IR (KBr): 3420, 1646, 1508, 1457, 1297, 1248, 832, 743 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O2 348.1707; Found 348.1707.

4-((1H-Indol-3-yl)methyl)-2-(4-fluorophenyl)-1,5-dimethyl-1,2-dihydro-3-pyrazol-3-one (3da)

Eluent: petroleum ether/ethyl acetate (1:2). Pink solid (80.5 mg, 80%); m.p. = 185–186 °C. 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.34–7.31 (m, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.07 (q, J = 7.8 Hz, 4H), 6.88 (s, 1H), 3.73 (s, 2H), 2.89 (s, 3H), 2.09 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 160.8 (d, J = 245 Hz), 153.4, 136.4, 131.3, 131.3, 127.0, 125.6 (d, J = 9 Hz), 122.6, 121.4, 118.7 (d, J = 9.0 Hz), 115.8 (d, J = 23.0 Hz), 113.4, 111.2, 109.9, 35.9, 18.1, 11.1. IR (KBr): 3245, 2922, 1646, 1541, 1430, 1221, 836, 743 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19FN3O 336.1507; Found 336.1507.

4-((1H-Indol-3-yl)methyl)-2-(4-chlorophenyl)-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3ea)

Eluent: petroleum ether/ethyl acetate (1:2). Pink solid (91.8 mg, 87%); m.p. = 188–189 °C. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.66 (s, 1H), 7.36 (s, 4H), 7.24 (s, 1H), 7.11 (s, 2H), 6.95 (s, 1H), 3.74 (s, 2H), 2.92 (s, 3H), 2.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 154.1, 136.4, 134.0, 131.5, 129.1, 127.1, 124.5, 122.5, 121.6, 119.0, 118.8, 113.6, 111.2, 110.5, 36.3, 18.1, 11.3. IR (KBr): 3420, 1646, 1489, 1339, 1148, 1090, 829, 742 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19ClN3O 352.1211; Found 352.1211.

4-((1H-Indol-3-yl)methyl)-2-(4-bromophenyl)-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3fa)

Eluent: petroleum ether/ethyl acetate (1:2). Pink solid (84.4 mg, 71%); m.p. = 192–193 °C. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 7.7 Hz, 1H), 7.13–7.05 (m, 2H), 6.92 (s, 1H), 3.75 (s, 2H), 2.92 (s, 3H), 2.13 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 154.2, 136.3, 134.5, 132.0, 127.0, 124.8, 122.5, 121.5, 119.3, 118.9, 118.7, 113.5, 111.2, 110.3, 36.2, 18.1, 11.2. IR (KBr): 3419, 1646, 1508, 1487, 1339, 1249, 1009, 742 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H19BrN3O 396.0706; Found 396.0706.

4-(4-((1H-Indol-3-yl)methyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)benzonitrile (3ga)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (52.4 mg, 51%); m.p. = 158–160 °C. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.70–7.64 (m, 3H), 7.57 (d, J = 8.6 Hz, 2H), 7.30–7.25 (m, 1H), 7.16–7.12 (m, 1H), 7.10–7.06 (m, 1H), 7.01 (s, 1H), 3.75 (s, 2H), 2.96 (s, 3H), 2.19 (s, 3H). 113C{1H} NMR (100 MHz, CDCl3) δ 166.3, 156.2, 139.4, 136.3, 133.0, 127.0, 122.3, 122.2, 121.7, 119.1, 118.7, 118.6, 113.2, 111.2, 111.1, 108.4, 37.0, 18.1, 11.4. IR (KBr): 3274, 2227, 1653, 1505, 1339, 1138, 840, 743 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H19N4O 343.1553; Found 343.1553.

4-((1H-indol-3-yl)methyl)-1,5-dimethyl-2-(4-(methylsulfonyl)phenyl)-1,2-dihydro-3H-pyrazol-3-one (3ha)

Eluent: petroleum ether/ethyl acetate (2:1). Orange solid (71.2 mg, 60%); m.p. = 211–212 °C. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.66–7.64 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 3.76 (s, 2H), 3.02 (s, 3H), 2.98 (s, 3H), 2.20 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 156.2, 140.2, 136.7, 136.3, 128.5, 127.0, 122.4, 122.3, 121.8, 119.2, 118.8, 113.5, 111.1, 111.1, 44.6, 37.0, 18.1, 11.5. IR (KBr): 3274, 2923, 1653, 1489, 1312, 1149, 769, 556 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O3S 396.1376; Found 396.1376.

4-((1H-Indol-3-yl)methyl)-1,5-dimethyl-2-(o-tolyl)-1,2-dihydro-3H-pyrazol-3-one (3ia)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (69.6 mg, 70%); m.p. = 136–137 °C. 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.67 (d, J = 7.3 Hz, 1H), 7.27–7.23 (m, 2H), 7.20 (s, 1H), 7.18–7.11 (m, 2H), 7.07–7.00 (m, 2H), 6.88 (s, 1H), 3.76 (s, 2H), 2.85 (s, 3H), 2.24 (s, 3H), 2.06 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.9, 151.1, 137.3, 136.4, 134.0, 131.1, 128.7, 128.1, 127.1, 126.6, 122.5, 121.2, 118.8, 118.6, 113.9, 111.3, 108.1, 34.4, 18.1, 17.8, 10.9. IR (KBr): 3227, 2922, 1635, 1489, 1457, 1256, 1100, 742 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O 332.1757; Found 332.1757.

4-((1H-Indol-3-yl)methyl)-1,5-dimethyl-2-(m-tolyl)-1,2-dihydro-3H-pyrazol-3-one (3ja)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (92.5 mg, 93%); m.p. = 156–157 °C. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.20–7.15 (m, 2H), 7.08–7.01 (m, 3H), 6.91 (s, 1H), 3.74 (s, 2H), 2.92 (s, 3H), 2.34 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 153.0, 139.0, 136.4, 135.1, 128.8, 127.1, 127.1, 124.6, 122.6, 121.3, 120.9, 118.8, 118.7, 113.6, 111.2, 109.9, 35.9, 21.3, 18.1, 11.1. IR (KBr): 3254, 2922, 1644, 1488, 1456, 1141, 784, 742 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O 332.1757; Found 332.1757.

4-((1H-Indol-3-yl)methyl)-2-(3,4-dimethylphenyl)-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3ka)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (87.1 mg, 84%); m.p. = 139–140 °C. 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 11.3 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.21–7.17 (m, 3H), 7.11–7.04 (m, 3H), 6.95 (s, 1H), 3.77 (s, 2H), 2.94 (s, 3H), 2.26 (s, 6H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 152.3, 137.4, 136.4, 135.1, 132.9, 130.1, 127.1, 125.5, 122.6, 121.7, 121.3, 118.8, 113.9, 111.2, 109.7, 35.7, 19.8, 19.3, 18.1, 11.1. IR (KBr): 3245, 2922, 2854, 1638, 1500, 1455, 1340, 741 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H24N3O 346.1914; Found 346.1914.

4-((1H-Indol-3-yl)methyl)-1,5-dimethyl-2-(naphthalen-2-yl)-1,2-dihydro-3H-pyrazol-3-one (3la)

Eluent: petroleum ether/ethyl acetate (1:1). Pink solid (95.9 mg, 87%); m.p. = 199–201 °C. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.88–7.85 (m, 3H), 7.75–7.73 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53–7.51 (m, 2H), 7.29–7.26 (m, 1H), 7.13–7.11 (m, 2H), 7.04 (s, 1H), 3.83 (s, 2H), 3.03 (s, 3H), 2.21 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 153.5, 136.4, 133.4, 132.9, 131.6, 128.9, 127.9, 127.6, 127.1, 126.5, 125.9, 122.5, 122.4, 121.5, 119.0, 118.8, 113.8, 111.2, 110.2, 36.3, 18.2, 11.3. IR (KBr): 3254, 2921, 1646, 1508, 1467, 1141, 816, 743 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C24H22N3O 368.1757; Found 368.1750.

4-((1H-Indol-3-yl)methyl)-1,2,5-trimethyl-1,2-dihydro-3H-pyrazol-3-one (3ma)

Eluent: petroleum ether/ethyl acetate (1:3). Red solid (59.7 mg, 78%); m.p. = 93–94 °C. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.09–7.05 (m, 1H), 6.97 (s, 1H), 3.72 (s, 2H), 3.30 (s, 3H), 3.11 (s, 3H), 2.05 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 149.0, 136.5, 127.1, 122.4 , 121.3 , 118.8, 118.7, 114.0, 111.2, 108.0, 33.6, 28.9, 18.0, 10.5. IR (KBr): 3364, 2921, 2851, 1602, 1457, 1435, 1338, 741 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C15H18N3O 256.1444; Found 256.1444.

4-((1H-Indol-3-yl)methyl)-2-isopropyl-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3na)

Eluent: petroleum ether/ethyl acetate (1:3). Red solid (62.9 mg, 74%); m.p. = 144–145 °C. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.63 (s, 1H), 7.26 (s, 1H), 7.07–7.05 (m, 2H), 6.86 (s, 1H), 4.52 (s, 1H), 3.67 (s, 2H), 3.03 (s, 3H), 1.97 (s, 3H), 1.39 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 151.8, 136.5, 127.2, 122.3, 121.3, 118.8, 118.7, 114.0, 111.2, 109.2, 47.6, 36.0, 20.8, 18.0, 10.9. IR (KBr): 3218, 2923, 1619, 1456, 1258, 1132, 1101, 744 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C17H22N3O 284.1757; Found 284.1758.

4-((1H-Indol-3-yl)methyl)-2-cyclohexyl-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3oa)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (77.6 mg, 80%); m.p. = 80–81 °C. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.14–7.04 (m, 2H), 6.95 (s, 1H), 4.03 (m, 1H), 3.69 (s, 2H), 3.06 (s, 3H), 2.01 (s, 3H), 1.97–1.90 (m, 1H), 1.82 (s, 4H), 1.72–1.66 (m, 1H), 1.43–1.17 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 168.2, 151.8, 136.4, 127.1, 122.3, 121.3, 118.8, 118.7, 114.1, 111.1, 109.4, 56.2, 36.1, 31.0, 26.2, 25.4, 18.0, 11.0. IR (KBr): 3245, 2929, 2854, 1616, 1455, 1340, 1234, 741 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H26N3O 324.2070; Found 324.2070.

4-((1H-Indol-3-yl)methyl)-1-ethyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3pa)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (71.6 mg, 72%); m.p. = 84–85 °C. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.43–7.40 (m, 4H), 7.25–7.19 (m, 2H), 7.10–7.02 (m, 2H), 6.87 (s, 1H), 3.78 (s, 2H), 3.50 (q, J = 6.8 Hz, 2H), 2.11 (s, 3H), 0.77 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.7, 151.8, 136.4, 135.2, 129.0, 127.1, 126.2, 123.9, 122.4, 121.3, 118.8, 118.7, 113.6, 111.3, 111.2, 42.4, 18.3, 11.0, 9.9. IR (KBr): 3419, 1639, 1496, 1456, 1429, 1075, 742, 697 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H22N3O 332.1757; Found 332.1757.

4-((1H-Indol-3-yl)methyl)-1-cyclopentyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3qa)

Eluent: petroleum ether/ethyl acetate (1:1). Orange solid (103.6 mg, 93%); m.p. = 243–244 °C. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.67 (s, 1H), 7.47 (s, 4H), 7.30 (s, 1H), 7.23 (s, 1H), 7.09 (s, 2H), 6.89 (s, 1H), 3.82 (s, 2H), 3.48 (s, 1H), 2.15 (s, 3H), 1.49–1.18 (m, 3H), 1.08–0.93 (m, 2H), 0.82–0.79 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 151.8, 136.4, 135.2, 128.9, 127.0, 126.3, 124.1, 122.5, 121.2, 118.6, 113.4, 111.2, 110.0, 47.4, 28.5, 25.2, 22.1, 18.3, 13.6, 11.0. IR (KBr): 3255, 2927, 1646, 1592, 1492, 1456, 741, 696 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C24H26N3O 372.2070; Found 372.2070.

4-((1H-Indol-3-yl)methyl)-1-benzyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ra)

Eluent: petroleum ether/ethyl acetate (1:1). Red solid (67.3 mg, 57%); m.p. = 78–79 °C. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.41 (s, 4H), 7.25–7.14 (m, 4H), 7.09–6.99 (m, 3H), 6.85 (d, J = 7.2 Hz, 2H), 6.59 (s, 1H), 4.60 (s, 2H), 3.70 (s, 2H), 2.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 152.0, 136.4, 135.2, 134.0, 129.1, 128.5, 128.0, 127.5, 127.1, 126.4, 124.1, 122.2, 121.4, 118.9, 118.7, 113.6, 111.3, 111.1, 51.0, 18.2, 11.6. IR (KBr): 3256, 2923, 1642, 1496, 1455, 1353, 741, 698 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C26H24N3O 394.1914; Found 394.1914.

4-((1H-Indol-3-yl)methyl)-1-isopropyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3sa)

Eluent: petroleum ether/ethyl acetate (1:2). Brown solid (62.2 mg, 60%); m.p. = 193–195 °C. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.46–7.44 (m, 4H), 7.26–7.22 (m, 2H), 7.13–7.07 (m, 2H), 6.90 (s, 1H), 3.84 (s, 2H), 3.18–3.11 (m, 1H), 3.04 (s, 3H), 1.27 (d, J = 7.2 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 161.7, 136.4, 135.2, 129.0, 127.1, 126.1, 123.7, 122.3, 121.5, 118.9, 118.8, 114.4, 111.1, 109.6, 37.3, 26.7, 20.5, 18.3. IR (KBr): 3244, 2925, 1646, 1496, 1456, 1339, 742, 700 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H24N3O 346.1914; Found 346.1914.

4-((1H-Indol-3-yl)methyl)-1-methyl-2-phenyl-5-propyl-1,2-dihydro-3H-pyrazol-3-one (3ta)

Eluent: petroleum ether/ethyl acetate (1:2). Red oily liquid (83.9 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.65 (s, 1H), 7.41 (s, 4H), 7.22 (s, 2H), 7.06 (s, 2H), 6.93 (s, 1H), 3.76 (s, 2H), 2.95 (s, 3H), 2.50 (s, 2H), 1.54–1.26 (m, 2H), 0.91 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 157.3, 136.4, 135.3, 129.0, 127.1, 126.1, 123.7, 122.5, 121.3, 118.7, 118.7, 113.8, 111.2, 109.9, 36.2, 27.1, 21.9, 18.1, 13.8. IR (KBr): 3269, 2962, 1646, 1496, 1456, 1437, 742, 696 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H24N3O 346.1914; Found 346.1914.

4-((1H-Indol-3-yl)methyl)-5-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3ua)

Eluent: petroleum ether/ethyl acetate (1:2). Red solid (69.0 mg, 67%); m.p. = 181–182 °C. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.42 (m, 4H), 7.24–7.22 (m, 2H), 7.10–7.07 (m, 2H), 6.97 (s, 1H), 3.82 (s, 2H), 3.09 (s, 3H), 1.57 (s, 1H), 0.98–0.96 (d, J = 7.1 Hz, 2H), 0.82–0.81 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 157.1, 136.3, 135.3, 129.0, 127.2, 126.1, 123.5, 122.6, 121.3, 118.7, 118.7, 114.0, 111.6, 111.2, 36.6, 18.1, 6.7, 5.7. IR (KBr): 3420, 3273, 1646, 1496, 1455, 1338, 742, 698 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H22N3O 344.1757; Found 344.1757.

4-((1H-Indol-3-yl)methyl)-1-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrazol-3-one (3va)

Eluent: petroleum ether/ethyl acetate (1:1). Pink solid (64.8 mg, 56%); m.p. = 232–234 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.56 (t, J = 7.2 Hz, 3H), 7.50–7.43 (m, 3H), 7.31–7.25 (m, 3H), 7.15–7.11 (m, 2H), 7.04 (dd, J = 14.9, 7.4 Hz, 2H), 3.91 (s, 2H), 2.97 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.5, 151.0, 136.3, 135.3, 129.9, 129.8, 129.1, 129.0, 127.9, 127.1, 126.1, 123.0, 122.5, 121.7, 119.1, 119.0, 113.9, 113.3, 111.0, 40.1, 18.9. IR (KBr): 3402, 2920, 2359, 1640, 1493, 1453, 1091, 738 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C23H20N3OS 386.1322; Found 386.1322.