Synthesis of Succinimide-Linked Indazol-3-ols Derived from Maleimides under Rh(III) Catalysis.

The structural modification of N-aryl indazolols as tautomers of N-aryl indazolones has been established as a hot topic in pharmaceutics and medicinal chemistry. We herein disclose the rhodium(III)-catalyzed 1,4-addition reaction of maleimides with N-aryl indazol-3-ols, which provides the succinimide-bearing indazol-3-ol scaffolds with complete regioselectivity and a good functional group tolerance. Notably, the versatility of this protocol is demonstrated by the use of drug-molecule-linked and fluorescence-probe-linked maleimides.

Introduction

The succinimide motif is a privileged core of antipsychotics, anticonvulsants, and aldose reductase inhibitors such as lurasidone, phensuximide, ethosuximide, and ranirestat (Figure ).[1] Therefore, the synthesis and biological evaluation of succinimide derivatives are important in the fields of medicinal chemistry and drug discovery.[2]

Figure 1

Succinimide-containing bioactive molecules.

With advances in C–H functionalization reactions,[3] investigations have recently been mainly made into the direct installation of bioactive scaffolds such as succinimides into pharmaceutically relevant molecules.[4] To address these issues, maleimides have been intensively employed as succinimide precursors in the transition-metal-catalyzed C(sp2)–H and C(sp3)–H alkylation reactions (Scheme ).[5] Mechanistically, succinimide adducts are generated via a 1,4-addition pathway, where the migratory insertion of internal olefins of maleimides is followed by the protonation of the C–metal intermediates. Alternatively, maleimides can undergo migratory insertion, syn-coplanarity arrangement, and β-hydride elimination or E1cB elimination to afford olefinated compounds,[6] which can be further trapped by internal nucleophiles through a Michael-type reaction to produce spirosuccinimides.[7]

Scheme 1

Installation of Succinimides via C–H Functionalization

(A) Installation of succnimides via C–H functionalization. (B) Indazol-3-ol-assisted incorporation of succinimides (this work).

Indazolones and their analogous have attracted great attention by virtue of their biological applications as anticancer, anti-inflammatory, analgesic, antipsychotic, antiviral, and antihyperlipidemic agents.[8] To this end, the transition-metal-catalyzed C–H modification of N-aryl indazol-3-ones with α-diazo carbonyls, alkynes, acrylates, and nitroalkenes has been explored.[9] Driven by our efforts toward the direct integration of two bioactive scaffolds via catalytic C–H functionalization,[10] we herein describe the Rh(III)-catalyzed 1,4-addition of maleimides with N-aryl indazolols as tautomers of N-aryl indazolones, which rapid assembles succinimide-containing indazol-3-ols. The gram-scale experiments and synthetic transformations illustrate the practicality of the current methodology. Importantly, the developed protocol is highlighted by its application to drug-molecule-linked and fluorescence-probe-linked maleimides as coupling partners.

Results and Discussion

The reaction conditions were optimized by reacting N-aryl indazol-3-ol 1a and N-phenyl maleimide (2a) under Rh(III) catalysis. The results are summarized in Table . A cationic Rh(III) catalyst in the absence of external additives was found to be unreactive (Table , entry 1). To our delight, the combination of a cationic Rh(III) catalyst with HOAc promoted the reaction of 1a and 2a to afford 3a in a 51% yield (Table , entry 2). However, a 28% yield of 3a was formed in the absence of AgSbF6 under otherwise identical reaction conditions (Table , entry 3). These results indicated that a cationic [RhCp*Ln(SbF6)] catalyst (Ln = OAc or SbF6) might be an active catalyst in the catalytic cycle and the HOAc might facilitate the protonation step of a rhodacycle intermediate. Acid screening revealed that PivOH was found to be superior to HOAC and AdCO2H (Table , entries 4 and 5, respectively). Changing the silver additive to AgNTf2 gave a 32% yield of 3a (Table , entry 6). Evaluation of the solvents indicated that acetone was an optimal solvent, forming our desired product 3a in a 92% yield (Table , entries 7–10). Using a decreased amount of PivOH (50 mol %) resulted in the decreased formation of 3a, as shown in entry 11. Other catalysts such as Ru(II) and Co(III) were found to be less effective (Table , entries 12 and 13, respectively). Finally, using a lower loading of the Rh(III)Cp* catalyst (1 mol %) under otherwise identical conditions afforded 3a (56%), as shown in entry 14.

Table 1

Optimization of Reaction Conditionsa

entry	additive (mol %)	solvent	yield (%)b
1	AgSbF6 (10)	DCE	N.R.
2	AgSbF6 (10), AcOH (100)	DCE	51
3	AcOH (100)	DCE	28
4	AgSbF6 (10), PivOH (100)	DCE	62
5	AgSbF6 (10), AdCO2H (100)	DCE	45
6	AgNTf2 (10), PivOH (100)	DCE	32
7	AgSbF6 (10), PivOH (100)	MeCN	trace
8	AgSbF6 (10), PivOH (100)	EtOH	50
9	AgSbF6 (10), PivOH (100)	HFIP	30
10	AgSbF6 (10), PivOH (100)	acetone	92
11	AgSbF6 (10), PivOH (50)	acetone	62
12c	AgSbF6 (10), PivOH (100)	acetone	trace
13d	AgSbF6 (10), PivOH (100)	acetone	20
14e	AgSbF6 (10), PivOH (100)	acetone	56

Reaction conditions are as follows: 1a (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), additive (quantity noted), and solvent (1 mL) at 80 °C for 20 h under air in pressure tubes.

Yield by flash column chromatography.

[Ru(p-cymene)Cl2]2 (2.5 mol %) was used as a catalyst.

[CoCp*(CO)I2] (5 mol %) was used as a catalyst.

[RhCp*Cl2]2 (1 mol %) was used.

With the successful optimization results in hand, the substrate scope of maleimides and N-aryl indazol-3-ols was examined, as shown in Scheme . The reaction of N-aryl maleimides 2b and 2c with 1a provided the desired products 3b (95%) and 3c (76%), respectively. Linear and branched N-alkylated maleimides 2d–2g smoothly participated in the alkylation reaction at the ortho-C–H bond on the N-aryl ring of 1a, affording the corresponding products 3d–3g in high yields. In addition, this method could be applied to NH-free, N-benzyl, and N-allyl maleimides 2h–2j, producing 3h–3j, respectively, in 50–69% yields. Moreover, maleimide 2k derived from l-alanine amino ester was found to be a viable substrate in this transformation. To observe the difunctionalization and monofunctionalization on bis-maleimide 2l, the modified reaction conditions were first subjected into 1a. The desired product 3l was obtained in an 88% yield. The monofunctionalized product 3m was also obtained in a 60% yield under the standard reaction conditions along with a 12% yield of the bis-adduct 3l. Furthermore, the developed protocol was applied to the site-selective C–H functionalization of maleimides 2m–2p generated from complex drugs and a fluorescence probe. For examples, maleimide derivatives 2m (from metronidazole), 2n (from celecoxib), and 2o (from estrone) provided succinimide-linked drug molecules 3n–3p, respectively, in 50–72% yields. Additionally, a maleimide 2p with a fluorescence probe architecture was smoothly coupled with 1a to furnish 3q in a 50% yield.

Scheme 2

Substrate Scope of Maleimides and N-Aryl Indazol-3-ols

Reaction conditions are as follows: 1a–1n (0.2 mmol), 2a–2p (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), PivOH (100 mol %), and acetone (1 mL) at 80 °C for 20 h under air in pressure tubes.

Yield by flash column chromatography.

1a (0.6 mmol), 2l (0.2 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %), and PivOH (200 mol %) were used.

Bisalkylated adduct 3l was also obtained in a 12% yield.

[RhCp*(OAc)2] (5 mol %) was used in the absence of AgSbF6 under otherwise identical conditions.

After establishing a robust method for the C–H alkylation reaction using maleimides and N-phenyl indazol-3-ol (1a), the optimized reaction conditions were subsequently subjected into various N-aryl indazol-3-ols 1b–1l and N-methyl maleimide (2d). Regardless of the electronic property on the aryl ring, para-substituted N-aryl indazol-3-ols 1b–1g readily reacted with 2d to give 4b–4g. It is noteworthy that electron-deficient groups such as CF3 (1f) and NO2 (1g), which are functional groups that often cause problems in catalytic C–H functionalization reactions, were also suitable in this coupling reaction. Interestingly, the meta-NO2-substituted substrate 1h provided a significantly lower yield of 4h (13%) under the standard reaction conditions. After screening the reaction conditions, we found that compound 1h could be efficiently coupled with 2d using a neutral Rh(III)Cp*(OAc)2 catalyst, furnishing 4h in a 92% yield. Complete regioselectivity at less-congested C–H bonds was also observed in other meta-substituted substrates, namely 1i and 1j. The chemical structures of ortho-alkylated indazol-3-ols were elucidated by the X-ray crystallographic analysis of 4j (CCDC 2149880) (see the SI for details). Moreover, substrates 1k and 1l bearing C5-substituents on the indazol-3-ol ring were also viable in the C–H alkylation reaction. However, compound 1m with a pyrazolopyridin-3-ol backbone was completely unreactive, potentially due to the competitive coordination of both nitrogen atoms on indazole and the pyridine cores to the Rh(III) center. N-Heteroaryl-substituted indazol-3-ol 1n was also found to be an unfavorable substrate for this transformation, potentially due to the tight coordination of the two N atoms on 1n to the Rh catalyst in bidentate manner. It is noted sterically hindered maleimide 2q, maleate 2r as a cis-olefin, and dihydropyrrol-2-one 2s were also unsuccessful in this coupling reaction.

Subsequently, gram-scale experiments were performed by the reactions of 1a (1 g) with 2a and 2d, providing 3a (1.31 g, 71%) and 3d (1.16 g, 75%), respectively (Scheme ).

Scheme 3

Gram-Scale Experiments

To understand the mechanistic pathway, we performed deuterium labeling experiments (Scheme ). The reaction of 1a with 2d in the presence of CD3CO2D resulted in complete deuterium exchange (>99% D) at the otho-position of deuterio-1a, indicating the reversible cleavage of ortho-C–H bonds by a Rh(III) catalyst prior to olefin insertion. On the succinimide moiety (C4-position) of deuterio-3d, 70% deuteration was also observed, suggesting that the deuteration of the Rh–C bond of a reaction intermediate with CD3CO2D might be involved in the catalytic pathway. Incomplete deuterium labeling can be explained by enol–keto tautomerization. An intermolecular kinetic isotope effect (KIE) experiment was also performed by reacting 1a and deuterio-1a in the presence of 2a. A KIE (kH/kD) value of 1.7 was detected, thereby indicating that the C–H cleavage step might be involved in the rate-determining step. Based on preliminary mechanistic studies and literature precedent,[5] a plausible reaction mechanism is outlined. A cationic Rh(III) catalyst undergoes the C–H activation process with 1a to produce a rhodacycle intermediate A. The coordination and migratory insertion of maleimide 2a deliver a seven-membered rhodacycle intermediate C. Protonation with PivOH provides our desired product 3a and a recyclable Rh(III) catalyst.

Scheme 4

Mechanistic Investigation and Proposed Reaction Mechanism

To illustrate the synthetic utility of this protocol, a series of transformations were performed using a succinimide-containing indazol-3-ol 3d (Scheme ). Triflation of the hydroxyl group on the indazole architecture produced 5a in a 61% yield. Next, a synthesized adduct 5a was employed in the Pd-catalyzed hydrogenation using Et3SiH, and 6a was afforded in a 72% yield. In addition, the Suzuki arylation of 5a with arylboronic acid afforded 6b in a 78% yield. Finally, the treatment of 5a with benzimidazole provided the heteroarylated adduct 6c (40%) containing three bioactive scaffolds, namely indazole, benzimidazole, and succinimide.

Scheme 5

Synthetic Transformations

Condition A: 5a (0.2 mmol), Et3SiH (3 equiv), Pd2(dba)2 (10 mol %), LiCl (50 mol %), and DMF at 80 °C for 24 h. Condition B: 5a (0.2 mmol), (p-CF3)Ph-B(OH)2 (2 equiv), Pd(PPh3)4 (10 mol %), K2CO3 (1 equiv), and DMF/EtOH (2:1) at 90 °C for 1 h. Condition C: 5a (0.2 mmol), benzimidazole (1.2 equiv), Pd(PPh3)4 (20 mol %), K2CO3 (2 equiv) and toluene at 110 °C for 20 h.

Conclusion

In conclusion, we demonstrated the synthesis of succinimide-linked indazol-3-ol derivatives by reacting N-aryl indazol-3-ols and maleimides under Rh(III)Cp* catalysis. This methodology is highlighted by the site-selective alkylation with bioactive-molecule-linked and chemical-probe-linked maleimides. Gram-scale experiments, mechanistic investigations, and post-transformations of the synthesized product are also demonstrated. Good regioselectivity and functional-group compatibility were achieved.

Experimental Section

General Information

Commercial chemicals and reagents were employed without further purification unless otherwise stated. N-Aryl indazol-3-ols (1a–1l) were prepared according to the reported literature.[9c,11] Maleimides 2a–2i and 2p were purchased from TCI. Maleimides 2j–2l and 2q were prepared according to the reported literature.[12] Maleimides 2m–2o were prepared according to the reported literature.[7e] Maleate 2r was purchased from TCI. N-Methyl-1,5-dihydro-2H-pyrrol-2-one (2s) was prepared according to the reported literature.[7e,13] All the reactions were performed in an oil bath using an IKA universal hot plate magnetic stirrer. Sealed tubes (13 × 100 mm2) purchased from Fischer Scientific were dried in oven overnight and cooled at room temperature prior to use. Thin layer chromatography was carried out using plates coated with Kieselgel 60F254 (Merck). For flash column chromatography, E. Merck Kieselgel 60 (230–400 mesh) was used. Nuclear magnetic resonance spectra (1H, 13C, and 19F NMR) were recorded on Bruker Unity 300 and 400 MHz spectrometers in a CDCl3, acetone-d6, or DMSO-d6 solution. Chemical shifts are reported as parts per million (ppm). Resonance patterns are reported with the notations s (singlet), br (broad), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and m (multiplet). In addition, the notation br is used to indicate a broad signal. Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a Varian 2000 infrared spectrophotometer. Data are reported as inverse centimeters (cm–1). High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-600 spectrometer.

General Scheme, Procedures, and Characterization Data for the Synthesis of N-(Quinolinyl)indazol-3-ol (1n)

To an oven-dried round flask charged with isatoic anhydride (1na) (1.95 g, 12.0 mmol, 100 mol %) in EtOH (20 mL) was added 2-hydrazinoquinoline (1nb) (1.91 g, 12.0 mmol, 100 mol %) at room temperature under an air atmosphere. The reaction mixture was stirred for 3 h at 85 °C. The reaction mixture was kept at room temperature for 12 h, filtered, and washed with EtOH to obtain 1.42 g of 1nc as a white solid in a 45% yield. Next, to an oven-dried round flask charged with 1nc (1.4 g, 5.32 mmol, 100 mol %) was added HCl (1.0 M, 25 mL) at room temperature under an air atmosphere. The reaction mixture was stirred for 15 min at room temperature. Then, EtOH (25 mL) was added to the reaction mixture, and to the resulting mixture was added NaNO2 (1.86 g, 27 mmol, 5.08 equiv) in 15 mL of H2O dropwise at room temperature. The reaction mixture was stirred for 3 h at 85 °C. The resulting mixture was kept at room temperature for 12 h, filtered, and washed with EtOH and diethyl ether to provide 1.01 g of 1n in a 72% yield as a light yellow solid (Scheme ).

Scheme 6

Synthesis of N-(quinolinyl) indazol-3-ol (1n)

1-(Quinolin-2-yl)-1H-indazol-3-ol (1n)

Yield: 1.01 g (72%), light yellow solid; mp = 249.2–250.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.7 (brs, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.02–8.00 (m, 2H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.81 (dt, J = 8.0, 1.2 Hz, 1H), 7.75 (ddd, J = 10.0, 7.2, 1.6 Hz, 1H), 7.63 (ddd, J = 9.6, 6.8, 1.2 Hz, 1H), 7.49 (ddd, J = 9.2, 6.8, 1.2 Hz, 1H), 7.31 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.2, 152.4, 146.2, 139.5, 138.8, 130.3, 129.2, 127.9, 127.4, 125.1, 124.9, 122.2, 120.2, 116.6, 115.7, 112.3; IR (KBr) υ 3055, 2987, 1671, 1604, 1563, 1509, 916 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C16H11N3O 261.0902, found 261.0903.

General Procedure and Characterization Data for the ortho-Alkylation of N-Aryl Indazol-3-ols with Maleimides (3a–3q and 4b–4l)

To an oven-dried reaction tube charged with 1-phenyl-1H-indazol-3-ol (1a) (42.1 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), AgSbF6 (6.9 mg, 0.02 mmol, 10 mol %), PivOH (20.4 mg, 0.2 mmol, 100 mol %), and N-phenylmaleimide (2a) (69.3 mg, 0.4 mmol, 200 mol %) was added acetone (1 mL) under an air atmosphere. The resulting mixture was stirred in oil bath at 80 °C for 20 h. The reaction mixture was diluted with EtOAc (2 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/EtOAc = 4:1 to 1:1) to afford 3a (70.8 mg) in a 92% yield.

3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-1-phenylpyrrolidine-2,5-dione (3a)

Yield: 70.8 mg (92%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 110.8–113.6 °C; 1H NMR (400 MHz, acetone-d6/CDCl3 = 10:1) δ 9.76 (dt, J = 8.0, 1.2 Hz, 1H), 7.68–7.64 (m, 1H), 7.53–7.48 (m, 2H), 7.44–7.37 (m, 2H), 7.36–7.29 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (td, J = 7.6, 0.8 Hz, 1H), 7.09–7.06 (m, 2H), 4.50 (q, J = 6.4 Hz, 1H), 3.26 (dd, J = 17.6, 9.6 Hz, 1H), 3.09 (dd, J = 18.0, 6.0 Hz, 1H); 13C NMR (100 MHz, acetone-d6/CDCl3 = 10:1) δ 177.3, 175.5, 157.2, 143.6, 139.6, 137.2, 133.9, 131.8, 130.3, 129.5, 129.3, 129.1, 128.7, 128.4, 127.8, 121.2, 120.9, 114.8, 111.2, 44.5, 38.8; IR (KBr) υ 3056, 2925, 1710, 1616, 1540, 1498, 1382, 1267, 1178 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C23H17N3O3 383.1270, found 383.1267.

1-(4-Fluorophenyl)-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3b)

Yield: 76.4 mg (95%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 93.5–96.4 °C; 1H NMR (400 MHz, acetone-d6) δ 10.01 (brs, 1H), 7.75 (dt, J = 8.0, 1.2 Hz, 1H), 7.68–7.64 (m, 1H), 7.53–7.50 (m, 2H), 7.44–7.38 (m, 2H), 7.24 (dt, J = 8.8, 0.8 Hz, 1H), 7.16 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 7.14–7.08 (m, 4H), 4.49 (q, J = 6.4 Hz, 1H), 3.26 (dd, J = 17.6, 9.6 Hz, 1H), 3.10 (dd, J = 18.0, 6.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 177.2, 175.5, 162.6 (d, JC–F = 243.9 Hz), 157.1, 143.5, 139.6, 137.1, 132.0, 130.0 (d, JC–F = 3.3 Hz), 129.8 (d, JC–F = 8.7 Hz), 129.6, 129.5, 128.9, 128.4, 121.0 (d, JC–F = 27.4 Hz), 116.2, 115.9, 114.8, 111.2, 44.6, 38.8; 19F NMR (376 MHz, acetone-d6/CDCl3 = 10:1) δ −115.4 (s); IR (KBr) υ 3054, 2922, 1704, 1617, 1581, 1544, 1509, 1440, 1384, 1267, 1226, 1178 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C23H16FN3O3 401.1176, found 401.1171.

3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-1-(4-nitrophenyl)pyrrolidine-2,5-dione (3c)

Yield: 65.2 mg (76%); eluent (CH2Cl2/EtOAc = 4:1 to 1:2); light brown solid; mp = 148.6–150.8 °C; 1H NMR (400 MHz, acetone-d6) δ 10.1 (brs, 1H), 8.23–8.19 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.70–7.68 (m, 1H), 7.55–7.48 (m, 2H), 7.45–7.39 (m, 2H), 7.38–7.34 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 4.55 (q, J = 6.4 Hz, 1H), 3.32 (dd, J = 18.0, 10.0 Hz, 1H), 3.16 (dd, J = 18.0, 6.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 176.7, 175.0, 157.1, 147.5, 143.4, 139.4, 139.3, 136.7, 132.5, 129.8, 129.5, 129.1, 128.5, 128.2, 124.4, 121.3, 120.9, 114.7, 111.2, 44.9, 38.5; IR (KBr) υ 3056, 2929, 1714, 1614, 1523, 1494, 1440, 1373, 1340, 1267, 1159, 1110, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C23H16N4O5 428.1121, found 428.1118.

3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (3d)

Yield: 63.2 mg (98%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 109.8–112.6 °C; 1H NMR (400 MHz, acetone-d6) δ 9.86 (brs, 1H), 7.73 (dt, J = 8.4, 0.8 Hz, 1H), 7.52–7.46 (m, 3H), 7.42–7.38 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.14 (ddd, J = 9.2, 7.2, 0.8 Hz, 1H), 4.28 (q, J = 5.6 Hz, 1H), 3.06 (dd, J = 17.6, 9.6 Hz, 1H), 2.74 (dd, J = 18.0, 5.6 Hz, 1H), 2.71 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 178.2, 176.5, 156.9, 143.3, 139.6, 137.4, 131.4, 129.4, 129.3, 128.8, 128.3, 121.0, 120.8, 114.6, 111.0, 44.1, 38.6, 24.8; IR (KBr) υ 3060, 1698, 1617, 1542, 1440, 1382, 1288, 1230, 1120, 956 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C18H15N3O3 321.1113, found 321.1110.

1-Ethyl-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3e)

Yield: 49.6 mg (74%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 103.7–106.5 °C; 1H NMR (400 MHz, acetone-d6) δ 9.91 (brs, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.48–7.37 (m, 5H), 7.22 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 4.28 (q, J = 6.0 Hz, 1H), 3.37–3.23 (m, 2H), 3.06 (dd, J = 18.0, 9.6 Hz, 1H), 2.83 (dd, J = 17.6, 5.6 Hz, 1H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 178.0, 176.3, 157.1, 143.6, 139.7, 137.6, 131.3, 129.5, 129.4, 128.9, 128.4, 121.1, 120.9, 114.8, 111.2, 40.0, 38.8, 34.1, 13.0; IR (KBr) υ 3062, 2923, 1698, 1616, 1542, 1494, 1442, 1403, 1349, 1270, 1224, 1126, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C19H17N3O3 335.1270, found 335.1270.

1-(tert-Butyl)-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3f)

Yield: 55.4 mg (76%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); brown solid; mp = 95.2–98.1 °C; 1H NMR (400 MHz, acetone-d6) δ 7.73 (dt, J = 8.0, 1.2 Hz, 1H), 7.48–7.43 (m, 3H), 7.40 (ddd, J = 9.6, 6.8, 1.2 Hz, 1H), 7.35–7.32 (m, 1H), 7.20 (dt, J = 8.8, 0.8 Hz, 1H), 7.14 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 4.15 (q, J = 6.4 Hz, 1H), 2.97 (dd, J = 17.6, 9.6 Hz, 1H), 2.85 (dd, J = 17.6, 6.8 Hz, 1H), 1.37 (s, 9H); 13C NMR (100 MHz, acetone-d6) δ 178.3, 176.7, 156.3, 142.9, 138.9, 137.3, 130.3, 128.6, 128.4, 127.9, 127.6, 120.2, 119.9, 113.9, 110.5, 57.4, 43.2, 38.3, 27.5; IR (KBr) υ 3054, 2985, 1697, 1617, 1540, 1492, 1442, 1421, 1342, 1265, 1157, 1116, 1043, 956 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C21H21N3O3 363.1583, found 363.1581.

1-Cyclohexyl-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3g)

Yield: 56.2 mg (72%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); white solid; mp = 109.6–112.4 °C; 1H NMR (400 MHz, acetone-d6) δ 7.72 (dt, J = 8.0, 1.2 Hz, 1H), 7.48–7.43 (m, 3H), 7.40 (td, J = 8.4, 1.2 Hz, 1H), 7.36–7.34 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.14 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 4.22 (q, J = 6.0 Hz, 1H), 3.77 (tt, J = 16.0, 3.6 Hz, 1H), 3.03 (dd, J = 18.0, 9.6 Hz, 1H), 2.83 (dd, J = 18.0, 6.0 Hz, 1H), 2.03–1.96 (m, 1H), 1.90–1.85 (m, 1H), 1.73–1.67 (m, 2H), 1.59–1.56 (m, 1H), 1.40–1.36 (m, 2H), 1.28–1.17 (m, 2H), 1.08 (tt, J = 15.6, 2.8 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 178.3, 176.5, 157.2, 143.7, 139.8, 137.8, 130.9, 129.5, 129.3, 128.9, 128.4, 121.0, 120.8, 114.9, 112.2, 52.1, 43.6, 38.7, 29.2, 26.5, 25.9; IR (KBr) υ 3054, 2931, 1697, 1617, 1583, 1542, 1498, 1444, 1373, 1265, 1189, 1143 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C23H23N3O3 389.1739, found 389.1735.

3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3h)

Yield: 30.8 mg (50%); eluent (CH2Cl2/EtOAc = 4:1 to 1:4); light brown solid; mp = 137.7–140.4 °C; 1H NMR (400 MHz, acetone-d6) δ 10.01 (brs, 1H), 9.94 (brs, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.43–7.38 (m, 2H), 7.56–7.51 (m, 1H), 7.50–7.47 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 4.36 (q, J = 6.0 Hz, 1H), 3.08 (dd, J = 18.0, 9.6 Hz, 1H), 2.73 (dd, J = 18.4, 6.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 179.1, 177.2, 157.2, 143.5, 139.8, 137.2, 130.8, 129.4, 129.3, 128.9, 128.0, 121.0, 120.9, 114.8, 111.0, 45.0, 40.1; IR (KBr) υ 3056, 2918, 1712, 1614, 1538, 1463, 1436, 1328, 1267, 1228, 1180 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C17H13N3O3 307.0957, found 307.0957.

1-Benzyl-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3i)

Yield: 54.9 mg (69%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 171.6–174.4 °C; 1H NMR (400 MHz, acetone-d6) δ 10.04 (brs, 1H), 7.74 (dt, J = 8.0, 1.2 Hz, 1H), 7.15 (ddd, J = 8.0, 0.8 Hz, 1H), 7.50–7.39 (m, 5H), 7.27–7.21 (m, 6H), 4.54 (d, J = 14.4 Hz, 1H), 4.42–4.38 (m, 2H), 3.15 (dd, J = 18.0, 9.6 Hz, 1H), 2.79 (dd, J = 18.4, 5.6 Hz, 1H); 13C NMR (100 MHz, acetone-d60) δ 178.1, 176.3, 157.2, 143.4, 139.7, 137.5, 137.2, 130.9, 129.5, 129.4, 129.2, 128.9, 128.8, 128.3, 128.2, 121.1, 120.9, 114.7, 111.1, 43.8, 42.7, 38.7; IR (KBr) υ 3058, 2925, 1700, 1616, 1542, 1496, 1434, 1396, 1342, 1311, 1267, 1228, 1164, 1081, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C24H19N3O3 397.1426, found 397.1427.

1-Allyl-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (3j)

Yield: 45.2 mg (65%); eluent (CH2Cl2/EtOAc = 4:1 to 1:3); yellow oil; 1H NMR (400 MHz, acetone-d6) δ 9.98 (brs, 1H), 7.73 (dt, J = 8.0, 1.2 Hz, 1H), 7.51–7.45 (m, 3H), 7.42–7.38 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.67–5.57 (m, 1H), 5.10–4.98 (m, 2H), 4.35 (q, J = 5.6 Hz, 1H), 3.94–3.80 (m, 2H), 3.14 (dd, J = 18.0, 10.0 Hz, 1H), 2.82 (dd, J = 18.0, 6.0 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 177.8, 176.0, 157.1, 143.5, 139.7, 137.4, 132.6, 131.2, 129.5, 129.4, 128.9, 128.3, 121.1, 120.9, 117.2, 114.7, 111.1, 43.9, 41.3, 38.7; IR (KBr) υ 3060, 2927, 1697, 1616, 1587, 1540, 1498, 1428, 1392, 1330, 1268, 1228, 1197, 1176, 1130, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C20H17N3O3 347.1270, found 347.1266.

Methyl (S)-2-((R)-3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-2,5-dioxopyrrolidin-1-yl)propanoate (3k)

Yield: 56.8 mg (72%, dr = 1:1); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 110.4–113.3 °C; 1H NMR (400 MHz, acetone-d6) diastereomer A δ 7.76–7.73 (m, 1H), 7.50–7.47 (m, 3H), 7.44–7.39 (m, 2H), 7.30–7.26 (m, 1H), 7.18–7.14 (m, 1H), 4.78–4.71 (m, 1H), 4.35 (dd, J = 8.0, 4.0 Hz, 1H), 3.69 (s, 3H), 3.24–3.15 (m, 1H), 2.87 (dd, J = 16.0, 4.0 Hz, 1H), 1.37 (d, J = 4.0 Hz, 3H); 1H NMR (400 MHz, acetone-d6) diastereomer B δ 7.76–7.73 (m, 1H), 7.50–7.47 (m, 3H), 7.44–7.39 (m, 2H), 7.30–7.26 (m, 1H), 7.18–7.14 (m, 1H), 4.78–4.71 (m, 1H), 4.35 (dd, J = 8.0, 4.0 Hz, 1H), 3.65 (s, 3H), 3.24–3.15 (m, 1H), 2.79 (dd, J = 16.0, 4.0 Hz, 1H), 1.29 (d, J = 4.0 Hz, 3H); 13C NMR (100 MHz, acetone-d6) diastereomer A δ 177.7, 175.8, 170.6, 157.3, 143.6, 139.8, 137.1, 130.8, 129.6, 129.5, 129.0, 128.0, 121.2, 121.0, 114.9, 111.2, 52.8, 48.5, 43.6, 39.0, 14.2; 13C NMR (100 MHz, acetone-d6) diastereomer B: δ 177.5, 175.7, 170.5, 157.2, 143.4, 139.7, 136.9, 130.6, 129.5, 129.4, 128.9, 127.8, 121.1, 120.9, 114.8, 111.0, 52.7, 48.5, 43.3, 38.9, 14.1; IR (KBr) υ 3056, 2998, 1745, 1702, 1617, 1542, 1498, 1440, 1390, 1359, 1309, 1265, 1230, 1201, 1114, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C21H19N3O5 393.1325, found 393.1321.

3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-1-(2–3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)-2,5-dioxopyrrolidin-1-yl)ethyl)pyrrolidine-2,5-dione (3l)

Yield: 112.8 mg (88%); eluent (CH2Cl2/EtOAc = 6:1 to 2:1); light brown solid; mp = 217.0–219.9 °C; 1H NMR (400 MHz, acetone-d6) δ 9.96 (brs, 2H), 7.72 (dd, J = 8.0, 2.8 Hz, 2H), 7.55–7.51 (m, 2H), 7.48–7.36 (m, 8H), 7.25 (t, J = 9.6 Hz, 2H), 7.17–7.11 (m, 2H), 4.21–4.16 (m, 2H), 3.59–3.42 (m, 4H), 3.07–2.94 (m, 2H), 2.69–2.59 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 178.7, 178.6, 176.8, 157.2, 157.1, 143.4, 143.3, 139.7, 139.6, 136.9, 136.7, 131.2, 130.9, 129.5, 129.4, 129.0, 128.9, 128.0, 127.9, 121.2, 121.1, 121.0, 120.9 (two carbons overlap), 114.7, 114.6, 111.0, 110.9, 43.4, 43.1, 38.7, 38.6, 37.8, 37.7; IR (KBr) υ 3054, 2987, 1702, 1616, 1540, 1500, 1432, 1400, 1330, 1267, 1159, 1103 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C36H29N6O6 641.2149, found 641.2151.

1-(2-(3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-2,5-dioxopyrrolidin-1-yl)ethyl)-1H-pyrrole-2,5-dione (3m)

Yield: 51.7 mg (60%); eluent (CH2Cl2/EtOAc = 6:1 to 2:1); light brown sticky solid; 1H NMR (400 MHz, acetone-d6) δ 9.88 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56–7.52 (m, 1H), 7.51–7.46 (m, 2H), 7.44–7.38 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.83 (s, 2H), 4.23 (q, J = 6.0 Hz, 1H), 3.66–3.64 (m, 2H), 3.59–3.53 (m, 1H), 3.49–3.43 (m, 1H), 3.05 (dd, J = 18.0, 9.6 Hz, 1H), 2.64 (dd, J = 18.0, 5.6 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 178.3, 176.4, 171.7, 157.0, 143.3, 139.7, 136.8, 135.3, 131.1, 129.4, 128.9, 127.9, 121.1, 120.9, 114.6, 110.9, 43.5, 38.8, 38.2, 36.3; IR (KBr) υ 3060, 2927, 1698, 1616, 1587, 1540, 1500, 1436, 1394, 1357, 1332, 1267, 1228, 1201, 1147, 1097, 1049, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C23H18N4O5 430.1277, found 430.1278.

2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl-3-(3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)-2,5-dioxopyrrolidin-1-yl)propanoate (3n)

Yield: 75.6 mg (71%); eluent (CH2Cl2/EtOAc = 4:1 to EtOAc only); white sticky solid; 1H NMR (400 MHz, acetone-d6) δ 10.0 (brs, 1H), 7.89 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.52–7.38 (m, 4H), 7.24 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.84 (s, 1H), 4.70–4.66 (m, 2H), 4.45–4.41 (m, 2H), 4.29 (q, J = 6.0 Hz, 1H), 3.69 (t, J = 6.8 Hz, 1H), 3.56–3.44 (m, 2H), 3.06 (dd, J = 18.0, 9.6 Hz, 1H), 2.80–2.75 (m, 1H), 2.60 (t, J = 7.2 Hz, 1H), 2.03 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.9, 176.2, 171.0, 152.3, 139.8, 139.7, 136.9, 135.3, 133.5, 133.4, 131.6, 129.4, 129.3, 128.9, 128.1, 121.1, 120.9, 114.8, 111.1, 63.6, 45.8, 44.1, 38.7, 35.0, 33.3, 14.4; IR (KBr) υ 3054, 2983, 1704, 1610, 1529, 1509, 1465, 1363, 1313, 1265, 1187, 1070 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C26H25N6O7 533.1785, found 533.1785.

4-(1-(4-(Amino(λ1-oxidanyl)(oxo)-λ5-sulfanyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl-3-(3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)-2,5-dioxopyrrolidin-1-yl)propanoate (3o)

Yield: 109.4 mg (72%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); white sticky solid; 1H NMR (400 MHz, acetone-d6) δ 9.87 (s, 1H), 7.97–7.94 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.57–7.55 (m, 2H), 7.48–7.36 (m, 9H), 7.24 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.74 (brs, 2H), 5.11 (s, 2H), 4.27 (q, J = 5.6 Hz, 1H), 3.67–3.55 (m, 2H), 3.07 (dd, J = 18.0, 10.0 Hz, 1H), 2.76 (dd, J = 18.0, 5.6 Hz, 1H), 2.60–2.52 (m, 1H), 2.48–2.41 (m, 1H); 13C NMR (100 MHz, acetone-d6) δ 178.0, 176.2, 171.2, 157.0, 145.9, 145.6, 145.0, 144.9, 144.2, 143.8, 143.4, 142.7, 139.6, 138.6, 137.1, 131.4, 130.0, 129.5, 129.4, 129.3, 128.9, 128.2, 128.1, 126.7, 122.4 (q, JC–F = 267.0 Hz), 121.1, 120.9, 114.7, 111.1, 107.2 (q, JC–F = 1.3 Hz), 66.2, 43.9, 38.7, 35.2, 32.5; 19F NMR (376 MHz, acetone-d6) δ −62.8 (s); IR (KBr) υ 3257, 3058, 1700, 1616, 1594, 1540, 1500, 1469, 1442, 1403, 1344, 1267, 1234, 1159, 1095, 973 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C37H30F3N6O7S 759.1849, found 759.1843.

(8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl-3-((R)-3-(2-(3-hydroxy-1H-indazol-1-yl)phenyl)-2,5-dioxopyrrolidin-1-yl)propanoate (3p)

Yield: 63.2 mg (50%, dr = 1:1); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 141.7–144.2 °C; 1H NMR (400 MHz, acetone-d6) δ 7.75 (d, J = 8.0 Hz, 1H), 7.53–7.40 (m, 5H), 7.28 (t, J = 8.8 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 6.88–6.85 (m, 1H), 6.82–6.81 (m, 1H), 4.32 (q, J = 6.0 Hz, 1H), 3.74–3.66 (m, 2H), 3.13 (dd, J = 18.0, 9.6 Hz, 1H), 2.88–6.83 (m, 2H), 2.80–2.59 (m, 3H), 2.48–2.39 (m, 2H), 2.31–2.24 (m, 1H), 1.87–1.83 (m, 1H), 1.66–1.43 (m, 9H), 0.91 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 219.4, 178.1, 176.3, 170.2, 157.0, 149.6, 143.3, 139.6, 138.7, 138.3, 137.1, 131.4, 129.5, 129.4, 128.9, 128.1, 127.1, 122.5, 121.1, 120.9, 119.7, 114.7, 111.1, 51.1, 48.4, 45.0, 43.9, 38.9, 38.8, 36.1, 35.2, 32.7, 32.6, 30.6, 27.0, 26.5, 22.1, 14.1; IR (KBr) υ 3056, 2927, 1708, 1612, 1567, 1567, 1540, 1465, 1378, 1267, 1224, 1174, 1010 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C38H38N3O6 632.2761, found 632.2759.

3-(2-(3-Hydroxy-1H-indazol-1-yl)phenyl)-1-(pyren-1-yl)pyrrolidine-2,5-dione (3q)

Yield: 50.8 mg (50%, rotomer ratio 2:1); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 171.6–174.4 °C; 1H NMR (400 MHz, acetone-d6) rotomer A δ 10.1 (brs, 1H), 8.34–8.19 (m, 5H), 8.12–7.99 (m, 2H), 7.95–7.92 (m, 1H), 7.89–7.80 (m, 2H), 7.64–7.58 (m, 1H), 7.57–7.52 (m, 2H), 7.48–7.44 (m, 1H), 7.41–7.37 (m, 1H), 7.32–7.27 (m, 1H), 7.21 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 4.93 (dd, J = 10.0, 6.4 Hz, 1H), 3.59 (dd, J = 18.0, 9.6 Hz, 1H), 3.32 (dd, J = 18.0, 6.0 Hz, 1H); 1H NMR (400 MHz, acetone-d6) rotomer B δ 10.1 (brs, 1H), 8.34–8.19 (m, 5H), 8.12–7.99 (m, 2H), 7.95–7.92 (m, 1H), 7.89–7.80 (m, 2H), 7.64–7.58 (m, 1H), 7.57–7.52 (m, 2H), 7.48–7.44 (m, 1H), 7.41–7.37 (m, 1H), 7.32–7.27 (m, 1H), 7.16 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 4.81 (dd, J = 9.2, 6.8 Hz, 1H), 3.46 (dd, J = 18.0, 9.2 Hz, 1H), 3.39 (dd, J = 18.0, 6.8 Hz, 1H); 13C NMR (100 MHz, acetone-d6) rotomer A δ 178.4, 176.3, 157.6, 144.1, 140.4, 137.1, 132.6, 132.1, 131.9, 131.7, 130.9, 129.7, 129.6, 129.2, 129.1, 128.8, 128.4, 128.0, 127.5, 127.4, 126.8, 126.7, 125.8, 125.0, 123.2, 121.3, 121.1, 115.1, 111.4, 45.0, 39.5; 13C NMR (100 MHz, acetone-d6) rotomer B δ 178.1, 176.2, 157.3, 143.7, 139.9, 136.9, 132.5, 132.1, 131.8, 131.6, 130.9, 129.6, 129.5, 129.1, 129.0, 128.6, 128.2, 127.9, 127.4, 127.2, 126.7, 126.6, 125.7, 124.9, 122.9, 121.3, 120.9, 115.0, 111.3, 44.7, 39.4; IR (KBr) υ 3052, 2991, 1710, 1656, 1616, 1587, 1542, 1506, 1438, 1378, 1265, 1176, 1097, 1060, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C33H21N3O3 507.1583, found 507.1579.

3-(2-(3-Hydroxy-1H-indazol-1-yl)-5-methoxyphenyl)-1-methylpyrrolidine-2,5-dione (4b)

Yield: 57.2 mg (81%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 86.4–89.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.9 (brs, 1H), 7.68 (dt, J = 8.0, 1.2 Hz, 1H), 7.33 (ddd, J = 10.0, 7.2, 1.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.09–6.99 (m, 4H), 4.08 (dd, J = 9.6, 5.6 Hz, 1H), 3.82 (s, 3H), 2.90 (dd, J = 17.6, 9.6 Hz, 1H), 2.68 (dd, J = 17.6, 5.2 Hz, 1H), 2.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 177.3, 175.9, 159.1, 155.7, 142.2, 137.9, 130.9, 129.4, 127.7, 120.0, 119.6, 115.9, 113.7, 113.1, 109.8, 55.6, 42.9, 37.1, 24.4; IR (KBr) υ 3054, 2938, 1697, 1614, 1585, 1540, 1506, 1436, 1380, 1245, 1222, 1116, 1035, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C19H17N3O4 351.1219, found 351.1216.

3-(2-(3-Hydroxy-1H-indazol-1-yl)-5-methylphenyl)-1-methylpyrrolidine-2,5-dione (4c)

Yield: 47.2 mg (70%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); yellow solid; mp = 99.1–101.8 °C; 1H NMR (400 MHz, acetone-d6) δ 7.71 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.29–7.24 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 4.18 (dd, J = 9.6, 5.6 Hz, 1H), 3.03 (dd, J = 18.0, 9.6 Hz, 1H), 2.73 (dd, J = 18.0, 5.6 Hz, 1H), 2.68 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 178.2, 176.5, 156.9, 143.5, 139.5, 137.3, 136.9, 131.8, 129.9, 128.8, 128.4, 120.9, 120.8, 114.4, 111.0, 43.9, 38.6, 24.8, 21.1; IR (KBr) υ 3054, 2927, 1697, 1616, 1587, 1540, 1508, 1438, 1380, 1282, 1228, 1118, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C19H17N3O3 335.1270, found 335.1265.

3-(5-Chloro-2-(3-hydroxy-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (4d)

Yield: 65.5 mg (92%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 101.8–104.5 °C; 1H NMR (400 MHz, DMSO-d6/CDCl3 = 10:1) δ 10.1 (brs, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.4, 2.4 Hz, 1H), 7.43–7.37 (m, 2H), 7.19 (dd, J = 8.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 4.23 (q, J = 5.6 Hz, 1H), 2.96 (dd, J = 18.0, 9.6 Hz, 1H), 2.68–2.62 (m, 4H); 13C NMR (100 MHz, DMSO-d6/CDCl3 = 10:1) δ 177.2, 175.7, 156.2, 141.7, 137.7, 137.2, 132.5, 130.8, 128.9, 128.6, 128.1, 120.3, 120.2, 113.7, 109.8, 42.5, 37.1, 24.6; IR (KBr) υ 3054, 2929, 1698, 1616, 1581, 1536, 1494, 1438, 1380, 1267, 1228, 1189, 1118, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C18H14ClN3O3 355.0724, found 355.0721.

3-(5-Fluoro-2-(3-hydroxy-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (4e)

Yield: 57.7 mg (85%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 109.7–112.6 °C; 1H NMR (400 MHz, acetone-d6) δ 10.0 (brs, 1H), 7.72 (dt, J = 8.0, 1.2 Hz, 1H), 7.45 (dd, J = 8.8, 5.2 Hz, 1H), 7.42–7.40 (m, 1H), 7.38–7.35 (m, 1H), 7.27 (td, J = 8.0, 2.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.15 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 4.25 (q, J = 5.6 Hz, 1H), 3.03 (dd, J = 17.6, 9.6 Hz, 1H), 2.76 (dd, J = 18.0, 6.0 Hz, 1H), 2.70 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.7, 176.2, 162.8 (d, JC–F = 244.9 Hz), 157.1, 143.6, 140.1 (d, JC–F = 8.4 Hz), 135.9 (d, JC–F = 3.0 Hz), 130.5 (d, JC–F = 9.1 Hz), 128.9, 121.1, 120.8, 117.9 (d, JC–F = 23.5 Hz), 116.1 (d, JC–F = 22.6 Hz), 114.5, 110.9, 43.9 (d, JC–F = 1.2 Hz), 38.4, 24.9; 19F NMR (376 MHz, acetone-d6) δ −114.1 (s); IR (KBr) υ 3056, 2925, 1697, 1614, 1589, 1540, 1502, 1438, 1380, 1280, 1230, 1201, 1155, 1118, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C18H14FN3O3 339.1019, found 339.1020.

3-(2-(3-Hydroxy-1H-indazol-1-yl)-5-(trifluoromethyl)phenyl)-1-methylpyrrolidine-2,5-dione (4f)

Yield: 49.2 mg (63%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 80.0–82.9 °C; 1H NMR (400 MHz, acetone-d6) δ 7.94 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.45 (ddd, J = 9.6, 6.8, 1.2 Hz, 1H), 7.39 (dt, J = 8.4, 0.8 Hz, 1H), 7.20 (ddd, J = 9.2, 6.8, 0.8 Hz, 1H), 4.52 (dd, J = 9.6, 6.0 Hz, 1H), 3.16 (dd, J = 17.6, 9.6 Hz, 1H), 2.81 (dd, J = 18.0, 6.0 Hz, 1H), 2.77 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.8, 176.4, 157.6, 143.0, 142.9, 142.8, 137.3, 129.9 (q, JC–F = 32.4 Hz), 129.3, 129.1 (q, JC–F = 3.7 Hz), 128.1, 126.4 (q, JC–F = 3.8 Hz), 124.9 (q, JC–F = 270.0 Hz), 121.7, 121.1, 111.1, 44.2, 38.4, 24.9; 19F NMR (376 MHz, acetone-d6) δ −62.8 (s); IR (KBr) υ 3060, 2944, 1695, 1614, 1585, 1535, 1513, 1482, 1434, 1382, 1321, 1282, 1226, 1166, 1118, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C19H14F3N3O3 389.0987, found 389.0984.

3-(2-(3-Hydroxy-1H-indazol-1-yl)-5-nitrophenyl)-1-methylpyrrolidine-2,5-dione (4g)

Yield: 47.6 mg (65%); eluent (CH2Cl2/EtOAc = 4:1 to 1:4); yellow solid; mp = 275.8–278.7 °C; 1H NMR (400 MHz, acetone-d6) δ 11.3 (brs, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 8.4, 2.4 Hz, 1H), 7.80–7.77 (m, 2H), 7.50–7.44 (m, 2H), 7.21 (ddd, J = 10.0, 5.6, 1.6 Hz, 1H), 4.59 (q, J = 6.4 Hz, 1H), 3.09 (dd, J = 17.6, 9.6 Hz, 1H), 2.77 (s, 3H), 2.66 (dd, J = 18.0, 6.8 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 177.1, 175.8, 157.0, 145.5, 143.6, 140.9, 134.9, 128.7, 127.2, 126.6, 123.9, 121.1, 120.6, 114.6, 110.3, 43.2, 36.9, 24.7; IR (KBr) υ 3054, 2989, 1712, 1621, 1548, 1523, 1473, 1421, 1361, 1267, 1222, 1139, 1051, 898 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C18H15N4O5 367.1042, found 367.1039.

3-(2-(3-Hydroxy-1H-indazol-1-yl)-4-nitrophenyl)-1-methylpyrrolidine-2,5-dione (4h)

Yield: 67.4 mg (92%); eluent (CH2Cl2/EtOAc = 4:1 to 1:4); yellow solid; mp = 148.1–151.0 °C; 1H NMR (400 MHz, acetone-d6) δ 10.1 (brs, 1H), 8.30–8.27 (m, 2H), 7.85–7.83 (m, 1H), 7.77 (dt, J = 8.4, 0.8 Hz, 1H), 7.51–7.44 (m, 2H), 7.23 (ddd, J = 9.6, 6.4, 1.6 Hz, 1H), 4.54 (q, J = 6.0 Hz, 1H), 3.18 (dd, J = 17.6, 9.6 Hz, 1H), 2.80 (dd, J = 17.6, 5.6 Hz, 1H), 2.79 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.5, 176.1, 157.8, 148.6, 143.8, 143.2, 140.5, 133.0, 129.5, 123.4, 122.4, 121.9, 121.1, 115.3, 110.9, 44.2, 38.4, 25.0; IR (KBr) υ 3058, 2987, 1697, 1614, 1525, 1438, 1380, 1346, 1278, 1116, 954 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C18H15N4O5 367.1042, found 367.1039.

3-(4-Fluoro-2-(3-hydroxy-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (4i)

Yield: 61.2 mg (90%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); yellow solid; mp = 115.0–117.9 °C; 1H NMR (400 MHz, acetone-d6) δ 7.73 (dt, J = 8.0, 1.2 Hz, 1H), 7.58–7.54 (m, 1H), 7.43 (ddd, J = 10.0, 6.8, 1.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.27–7.22 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 4.30 (q, J = 5.6 Hz, 1H), 3.07 (dd, J = 18.0, 9.6 Hz, 1H), 2.76–2.70 (m, 4H); 13C NMR (100 MHz, acetone-d6) δ 178.2, 176.5, 162.6 (d, JC–F = 245.5 Hz), 157.4, 143.1, 140.8 (d, JC–F = 9.8 Hz), 133.1 (d, JC–F = 12.4 Hz), 133.0, 129.2, 121.4, 120.9, 116.1 (d, JC–F = 48.1 Hz), 115.0, 114.8 (d, JC–F = 4.6 Hz), 110. 9, 43.5, 38.5, 24.9; 19F NMR (376 MHz, acetone-d6) δ −114.3 (s); IR (KBr) υ 3056, 2927, 1697, 1612, 1504, 1438, 1380, 1243, 1191, 1060 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C18H14FN3O3 339.1019, found 339.1019.

3-(4-Chloro-2-(3-hydroxy-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (4j)

Yield: 64.9 mg (91%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); light brown solid; mp = 184.3–187.0 °C; 1H NMR (400 MHz, acetone-d6/CDCl3 = 10:1) δ 10.1 (s, 1H), 7.74 (dt, J = 8.0, 1.2 Hz, 1H), 7.53 (dd, J = 8.4, 0.8 Hz, 1H), 7.50–7.41 (m, 2H), 7.44 (ddd, J = 9.6, 6.8, 1.2 Hz, 1H), 7.31 (t, J = 8.4, 1.2 Hz, 1H), 7.17 (ddd, J = 8.8, 6.8, 0.8 Hz, 1H), 4.31 (dd, J = 9.6, 5.6 Hz, 1H), 3.08 (dd, J = 18.0, 9.6 Hz, 1H), 2.77–2.71 (m, 4H); 13C NMR (100 MHz, acetone-d6/CDCl3 = 10:1) δ 177.9, 176.3, 157.5, 143.2, 140.7, 135.9, 133.9, 132.9, 129.3, 129.2, 127.9, 121.5, 120.9, 114.9, 110.9, 43.6, 38.4, 24.9; IR (KBr) υ 3054, 2942, 1697, 1617, 1540, 1490, 1438, 1419, 1380, 1268, 1226, 1116, 1058, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C18H14ClN3O3 355.0724, found 355.0721.

3-(2-(3-Hydroxy-5-methyl-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (4k)

Yield: 55.7 mg (83%); eluent (CH2Cl2/EtOAc = 4:1 to 1:1); brown solid; mp = 139.3–142.2 °C; 1H NMR (400 MHz, acetone-d6) δ 7.50–7.43 (m, 4H), 7.39–7.36 (m, 1H), 7.23 (dd, J = 8.8, 1.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.28 (q, J = 5.6 Hz, 1H), 3.05 (dd, J = 18.0, 9.6 Hz, 1H), 2.76–2.70 (m, 4H), 2.42 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 178.3, 176.6, 156.8, 142.2, 139.7, 137.2, 131.3, 130.9, 130.5, 129.3, 129.2, 128.1, 119.9, 114.8, 110.9, 44.0, 38.6, 24.8, 21.1; IR (KBr) υ 3054, 2925, 1697, 1627, 1581, 1540, 1496, 1438, 1380, 1284, 1268, 1232, 1118, 956 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C19H17N3O3 335.1270, found 335.1265.

3-(2-(3-Hydroxy-5-nitro-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (4l)

Yield: 56.4 mg (77%); eluent (CH2Cl2/EtOAc = 4:1 to 1:2); yellow solid; mp = 217.0–219.8 °C; 1H NMR (400 MHz, acetone-d6) δ 10.6 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 9.6, 2.4 Hz, 1H), 7.58–7.50 (m, 4H), 7.37 (d, J = 9.2 Hz, 1H), 4.25 (q, J = 5.6 Hz, 1H), 3.09 (dd, J = 18.0, 9.6 Hz, 1H), 2.80 (dd, J = 18.0, 5.6 Hz, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.9, 176.3, 158.3, 144.5, 142.6, 138.3, 137.6, 131.7, 130.5, 129.7, 128.7, 123.6, 118.7, 113.8, 111.7, 43.9, 38.5, 24.8; IR (KBr) υ 3073, 2942, 1697, 1614, 1546, 1519, 1440, 1382, 1336, 1284, 1137, 1122, 1052, 958 cm–1; HRMS (ion trap, FAB) m/z [M + H]+ Calcd for C18H15N4O5 367.1042, found 367.1040.

General Procedure for the Gram-Scale Reaction of 3a

To an oven-dried reaction tube charged with 1a (1.0 g, 4.8 mmol, 100 mol %), [RhCp*Cl2]2 (74.2 mg, 0.12 mmol, 2.5 mol %), AgSbF6 (165.0 mg, 0.48 mmol, 10 mol %), PivOH (490.2 mg, 4.8 mmol, 100 mol %), and N-phenyl maleimide (2a) (1.66 g, 9.6 mmol, 200 mol %) was added acetone (24 mL) under an air atmosphere. The resulting mixture was stirred in an oil bath for 20 h at 80 °C. The reaction mixture was diluted with EtOAc (20 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/EtOAc = 4:1 to 1:1) to afford 3a (1.31 g) in a 71% yield.

General Procedure for the Gram-Scale Reaction of 3d

To an oven-dried reaction tube charged with 1a (1.0 g, 4.8 mmol, 100 mol %), [RhCp*Cl2]2 (74.2 mg, 0.12 mmol, 2.5 mol %), AgSbF6 (165.0 mg, 0.48 mmol, 10 mol %), PivOH (490.2 mg, 4.8 mmol, 100 mol %), and N-methyl maleimide (2d) (1.07 g, 9.6 mmol, 200 mol %) was added acetone (24 mL) under an air atmosphere. The resulting mixture was stirred in an oil bath for 20 h at 80 °C. The reaction mixture was diluted with EtOAc (20 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/EtOAc = 4:1 to 1:1) to afford 3d (1.16 g) in a 75% yield.

General Procedure for the Deuterium Labeling Experiment

To an oven-dried sealed tube charged with 1-phenyl-1H-indazol-3-ol (1a) (42.1 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), AgSbF6 (6.9 mg, 0.02 mmol, 10 mol %), N-methyl maleimide (2d) (44.4 mg, 0.4 mmol, 200 mol %), and acetic acid-d4 (122.1 μL, 2.0 mmol, 10 equiv) was added acetone-d6 (1 mL) under an air atmosphere. The resulting mixture was stirred in an oil bath for 4 h at 80 °C. The resulting mixture was diluted with EtOAc (2 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/EtOAc = 8:1 to 1:3) to provide deuterio-1a (30.2 mg, 71%) and deuterio-3d (14.9 mg, 23%).

General Procedure for Intermolecular KIE Experiment

To an oven-dried reaction tube charged with 1a (21.0 mg, 0.1 mmol, 50 mol %), deuterio-1a (21.2 mg, 0.1 mmol, 50 mol %, >99% D), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), AgSbF6 (6.9 mg, 0.02 mmol, 10 mol %), N-methyl maleimide (2d) (44.4 mg, 0.4 mmol, 200 mol %), and acetic acid-d4 (122.1 μL, 2.0 mmol, 10 equiv) was added acetone-d6 (1 mL) under an air atmosphere. The reaction mixture was stirred in an oil bath for 3 h at 80 °C. The resulting mixture was diluted with EtOAc (2 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/EtOAc = 10:1 to 3:1) to provide 3d/deuterio-3d′ (10.4 mg) in a 16% yield. The KIE (kH/kD = 1.7) value was calculated from the relative intensity of ortho-C–H and ortho-C–D (7.402 ppm) on 3d and deuterio-3d′, respectively.

General Procedure and Characterization Data for the Triflation of 3d

To an oven-dried reaction tube charged with 3d (321.3 mg, 1.0 mmol, 100 mol %) and trifluoromethanesulfonic anhydride (423.2 mg, 1.5 mmol, 150 mol %) was added CH2Cl2 (10 mL) under an air atmosphere at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc (10 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 6:1 to 2:1) to afford 5a (276.6 mg) in a 61% yield.

1-(2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)phenyl)-1H-indazol-3-yl trifluoromethanesulfonatene (5a)

Yield: 276.6 mg (61%); eluent (n-hexanes/EtOAc = 6:1 to 2:1); yellow oil; 1H NMR (400 MHz, acetone-d6) δ 7.87 (d, J = 8.0 Hz, 1H), 7.66–7.57 (m, 5H), 7.48–7.44 (m, 2H), 4.10 (q, J = 5.6 Hz, 1H), 3.03 (dd, J = 18.0, 9.6 Hz, 1H), 2.77–2.71 (m, 4H); 13C NMR (100 MHz, acetone-d6) δ 177.8, 176.0, 147.3, 143.5, 137.9, 137.7, 131.3, 131.1, 130.2, 129.8, 129.1, 124.5, 119.6 (q, JC–F = 318.5 Hz), 119.1, 114.5, 112.3, 43.2, 38.5, 24.9; 19F NMR (376 MHz, CDCl3) δ −73.3 (s); IR (KBr) υ 3060, 2944, 1700, 1619, 1508, 1475, 1428, 1382, 1365, 1282, 1218, 1133, 1072, 956 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C19H14F3N3O5S 453.0606, found 453.0604.

General Procedure and Characterization Data for the Hydrogenation of 5a

To an oven-dried reaction tube charged with 5a (90.7 mg, 0.2 mmol, 100 mol %), Pd(dba)2 (11.5 mg, 0.02 mmol, 10 mol %), LiCl (4.2 mg, 0.1 mmol, 50 mol %), and DMF (1 mL) was added Et3SiH (95.8 μL, 0.6 mmol, 3 equiv) dropwise under an air atmosphere. The resulting mixture was stirred in an oil bath for 24 h at 80 °C. The resulting mixture was extracted with brine and EtOAc (3 × 10 mL). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 6:1 to 2:1) to afford 6a (44.2 mg) in a 72% yield.

3-(2-(1H-Indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (6a)

Yield: 44.2 mg (72%); eluent (n-hexanes/EtOAc = 6:1 to 2:1); yellow oil; 1H NMR (400 MHz, acetone-d6) δ 8.19 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.60–7.54 (m, 3H), 7.48–7.41 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 4.14 (q, J = 5.6 Hz, 1H), 2.97 (dd, J = 18.0, 9.6 Hz, 1H), 2.74 (dd, J = 17.2, 4.8 Hz, 1H), 2.61 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.8, 176.3, 141.6, 139.2, 137.4, 135.8, 131.8, 130.2, 129.5, 128.7, 127.9, 125.3, 122.4, 121.8, 111.2, 44.1, 38.4, 24.8; IR (KBr) υ 3056, 2989, 1710, 1616, 1565, 1506, 1477, 1421, 1361, 1324, 1268, 1222, 1166, 1118, 1066 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C18H15N3O2 305.1164, found 305.1164.

General Procedure and Characterization Data for the Suzuki Arylation Reaction of 5a

To an oven-dried reaction tube charged with 5a (90.7 mg, 0.2 mmol, 100 mol %), 4-(trifluoromethyl)phenylboronic acid (76.0 mg, 0.4 mmol, 200 mol %), Pd(PPh3)4 (23.1 mg, 0.02 mmol, 10 mol %), and K2CO3 (27.6 mg, 0.2 mmol, 1 equiv) was added DMF/EtOH (2:1, 1 mL) under a N2 atmosphere at room temperature. The resulting mixture was stirred in an oil bath for 1 h at 90 °C under a N2 atmosphere. The resulting mixture was extracted with brine and EtOAc (3 × 10 mL). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 3:1 to 2:1) to afford 6b (70.2 mg) in a 78% yield.

1-Methyl-3-(2-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)pyrrolidine-2,5-dione (6b)

Yield: 70.2 mg (78%); eluent (n-hexanes/EtOAc = 3:1 to 2:1); white solid; mp = 92.5–95.2 °C; 1H NMR (400 MHz, acetone-d6) δ 8.29 (d, J = 8.0 Hz, 2H), 8.23 (d, J = 8.4 Hz, 1H), 7.90–7.88 (m, 2H), 7.66–7.56 (m, 4H), 7.53 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.23 (q, J = 5.6 Hz, 1H), 3.06 (dd, J = 17.6, 9.6 Hz, 1H), 2.84 (dd, J = 18.0, 5.6 Hz, 1H), 2.50 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.7, 176.1, 144.5, 143.4, 138.7, 137.9 (q, JC–F = 5.6 Hz), 137.6, 132.0, 130.5, 130.2 (q, JC–F = 31.7 Hz), 129.6, 125.4 (q, JC–F = 269.7 Hz), 128.9, 128.7, 128.4, 126.6 (q, JC–F = 3.8 Hz), 123.6, 122.5, 121.7, 111.9, 44.2, 38.6, 24.7; 19F NMR (376 MHz, CDCl3) δ −62.9 (s); IR (KBr) υ 3058, 2987, 1693, 1614, 1502, 1434, 1417, 1380, 1280, 1222, 1118, 985, 952 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C25H18F3N3O2 449.1351, found 449.1347.

Experimental Procedure and Characterization Data for the Heteroarylation Reaction of 5a

To an oven-dried sealed tube charged with 5a (90.7 mg, 0.2 mmol, 100 mol %), benzimidazole (28.4 mg, 0.24 mmol, 120 mol %), Pd(PPh3)4 (46.2 mg, 0.04 mmol, 20 mol %), and K2CO3 (55.3 mg, 0.4 mmol, 2 equiv) was added toluene (1 mL) under a N2 atmosphere at room temperature. The reaction mixture was allowed to stir in an oil bath for 20 h at 110 °C under a N2 atmosphere. The reaction mixture was diluted with EtOAc (2 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 1:1 to 1:3) to afford 6c (33.8 mg) in a 40% yield.

3-(2-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-1-yl)phenyl)-1-methylpyrrolidine-2,5-dione (6c)

Yield: 33.8 mg (40%); eluent (n-hexanes/EtOAc = 1:1 to 1:3); white sticky oil; 1H NMR (400 MHz, acetone-d6) δ 11.9 (brs, 1H), 8.76 (d, J = 8.0 Hz, 1H), 7.69 (brs, 2H), 7.64–7.62 (m, 4H), 7.55 (ddd, J = 9.6, 6.8, 1.2 Hz, 1H), 7.46–7.41 (m, 2H), 7.29–7.25 (m, 2H), 4.22 (q, J = 5.6 Hz, 1H), 3.06 (dd, J = 18.0, 9.6 Hz, 1H), 2.84 (dd, J = 18.0, 5.6 Hz, 1H), 2.58 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.8, 176.3, 147.3 (two carbons overlap), 143.2 (two carbons overlap), 138.8 (two carbons overlap), 138.5, 137.9 (two carbons overlap), 131.4, 130.8 (two carbons overlap), 129.6, 129.0, 128.9 (two carbons overlap), 123.8, 123.7, 123.3, 111.5, 43.7, 38.8, 24.8; IR (KBr) υ 3054, 2987, 1710, 1621, 1540, 1523, 1469, 1421, 1361, 1267, 1222, 1170, 1137, 1089, 1052, 985, 954 cm–1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C25H19N5O2 421.1539, found 421.1537.