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). 1 Therefore, the synthesis and biological evaluation of succinimide derivatives are important in the fields of medicinal chemistry and drug discovery. 2 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(sp 2 )−H and C(sp 3 )−H alkylation reactions (Scheme 1). 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, syncoplanarity arrangement, and β-hydride elimination or E1cB elimination to afford olefinated compounds, 6 which can be further trapped by internal nucleophiles through a Michaeltype reaction to produce spirosuccinimides. 7 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-metalcatalyzed C−H modification of N-aryl indazol-3-ones with αdiazo 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 high-lighted 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 1. A cationic Rh(III) catalyst in the absence of external additives was found to be unreactive (Table 1, 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 1, entry 2). However, a 28% yield of 3a was formed in the absence of AgSbF 6 under otherwise identical reaction conditions (Table 1, entry 3). These results indicated that a cationic [RhCp*Ln(SbF 6 )] catalyst (Ln = OAc or SbF 6 ) 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 AdCO 2 H (Table 1, entries 4 and 5, respectively). Changing the silver additive to AgNTf 2 gave a 32% yield of 3a (Table 1, entry 6). Evaluation of the solvents indicated that acetone was an optimal solvent, forming our desired product 3a in a 92% yield (Table 1, 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 1, 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.
With the successful optimization results in hand, the substrate scope of maleimides and N-aryl indazol-3-ols was examined, as shown in Scheme 2. The reaction of N-aryl maleimides 2b and 2c with 1a provided the desired products 3b (95%) and 3c (76%), respectively. Linear and branched Nalkylated 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.
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 electrondeficient groups such as CF 3 (1f) and NO 2 (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-NO 2 -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 lesscongested 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 C5substituents 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 cisolefin, 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 3).
To understand the mechanistic pathway, we performed deuterium labeling experiments (Scheme 4). The reaction of 1a with 2d in the presence of CD 3 CO 2 D 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 CD 3 CO 2 D 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 (k H /k D ) value of 1.7 was Scheme 2. Substrate Scope of Maleimides and N-Aryl Indazol-3-ols a a Reaction conditions are as follows: 1a−1n (0.2 mmol), 2a−2p (0.4 mmol), [RhCp*Cl 2 ] 2 (2.5 mol %), AgSbF 6 (10 mol %), PivOH (100 mol %), and acetone (1 mL) at 80°C for 20 h under air in pressure tubes. b Yield by flash column chromatography. c 1a (0.6 mmol), 2l (0.2 mmol), [RhCp*Cl 2 ] 2 (5 mol %), AgSbF 6 (20 mol %), and PivOH (200 mol %) were used. d Bisalkylated adduct 3l was also obtained in a 12% yield. e [RhCp*(OAc) 2 ] (5 mol %) was used in the absence of AgSbF 6 under otherwise identical conditions. 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.
To illustrate the synthetic utility of this protocol, a series of transformations were performed using a succinimide-containing indazol-3-ol 3d (Scheme 5). Triflation of the hydroxyl group on the indazole architecture produced 5a in a 61% yield. Next, a synthesized adduct 5a was employed in the Pdcatalyzed hydrogenation using Et 3 SiH, 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.

■ CONCLUSION
In conclusion, we demonstrated the synthesis of succinimidelinked 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 bioactivemolecule-linked and chemical-probe-linked maleimides. Gramscale 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 ( 1 H, 13 C, and 19 F NMR) were recorded on Bruker Unity 300 and 400 MHz spectrometers in a CDCl 3 , acetone-d 6 , or DMSO-d 6 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 Scheme 4. Mechanistic Investigation and Proposed Reaction Mechanism Scheme 5. Synthetic Transformations a 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 ). Highresolution mass spectra (HRMS) were recorded on a JEOL JMS-600 spectrometer.