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. 2022 Apr 21;7(17):14712-14722.
doi: 10.1021/acsomega.1c07363. eCollection 2022 May 3.

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

Ju Young Kang  1 , Suho Kim  1 , Junghyea Moon  1 , Eunjae Chung  1 , Jaeyoung Kim  1 , So Young Kyung  1 , Hyung Sik Kim  1 , Neeraj Kumar Mishra  1 , In Su Kim  1
Affiliations

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

Ju Young Kang et al. ACS Omega. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Succinimide-containing bioactive molecules.
Scheme 1
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).
Scheme 2
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.
Scheme 3
Scheme 3. Gram-Scale Experiments
Scheme 4
Scheme 4. Mechanistic Investigation and Proposed Reaction Mechanism
Scheme 5
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.
Scheme 6
Scheme 6. Synthesis of N-(quinolinyl) indazol-3-ol (1n)
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