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. 2024 Jul 4;15(31):12442-12450.
doi: 10.1039/d4sc03739a. eCollection 2024 Aug 7.

Unified ionic and radical C-4 alkylation and arylation of pyridines

Qiu Shi  1 , Xiaofeng Huang  1 , Ruizhi Yang  1 , Wenbo H Liu  1
Affiliations

Unified ionic and radical C-4 alkylation and arylation of pyridines

Qiu Shi et al. Chem Sci. .

Abstract

C-H Functionalization of pyridines is an efficient strategy to access pyridine derivatives occurring in pharmaceuticals, agrochemicals, and materials. Nucleophilic additions to pyridiniums via both ionic and radical species have proven particularly useful. However, these reactions suffer from poor regioselectivity. By identifying an enzyme-mimic pocket-type urea activation reagent, we report a general platform for pyridine C-4 functionalization. Both ionic and radical nucleophiles can be incorporated to achieve the alkylation and arylation. Notably, the highly regioselective C-4 radical arylation is disclosed for the first time. The broad scope of nucleophiles and pyridines renders this platform applicable to the late-stage functionalization of drug-like molecules and the preparation of complex biologically important molecules.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Background and this work.
Fig. 2
Fig. 2. Design strategy and evaluation of diverse ureas with different structures. The yields and ratio of regioisomers were determined by 1H NMR. Please see ESI for experimental details.
Fig. 3
Fig. 3. Scope of Grignard reagents. The yields refer to the isolated yields of pure compounds. The ratios were determined by 1H NMR and GC-MS. Due to the low boiling points, the yields of 5c and 5f were determined by 1H NMR. Please see ESI for experimental details.
Fig. 4
Fig. 4. Scope of pyridines with Grignard as the nucleophile. The yields refer to the isolated yields of pure compounds in one pot from pyridine. The ratios were determined by 1H NMR and GC-MS. Please see ESI for experimental details.
Fig. 5
Fig. 5. Other feasible nucleophiles for C-4 functionalization. The yields refer to the isolated yields of pure compounds. The ratios were determined by 1H NMR and GC-MS. Please see ESI for experimental details.
Fig. 6
Fig. 6. Scope of radical precursors for C-4 functionalization. The yields refer to the isolated yields of pure compounds. The ratios were determined by 1H NMR and GC-MS.
Fig. 7
Fig. 7. Late-stage functionalization of drug-like molecules. All the yields refer to isolated one-pot yields from pyridines based on the recovered starting materials. The yields in the bracket are the isolated yields.
Fig. 8
Fig. 8. Target-oriented synthesis of biologically active molecules via this C-4 functionalization as key steps.
See this image and copyright information in PMC

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