C3-Selective Trifluoromethylthiolation and Difluoromethylthiolation of Pyridines and Pyridine Drugs via Dihydropyridine Intermediates

Zhou, Xin-Yue; Zhang, Ming; Liu, Zhong; He, Jia-Hao; Wang, Xiao‐Chen

doi:10.1021/jacs.2c06776

Cited by 63 publications

(31 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The ensuing electrophilic reactions and subsequent rearomatization provide exclusively meta-substituted heteroarenes (Fig. 1C) (26)(27)(28)(29)(30)(31). Several strategies for the reductive dearomatization of pyridines have been developed along those lines (32,33).…”

mentioning

confidence: 99%

“…For example, the interrupted reductive dearomatization of pyridiniums allowed for subsequent selective C3-functionalization, but tetrahydropyridines instead of the aromatized heteroarenes were formed as the final products (34). meta-Selective silylation, alkylation, and trifluoromethylthiolation have been developed through 1,4-reduction of pyridines by silanes or boranes followed by in situ functionalization and oxidative rearomatization (28)(29)(30). Nevertheless, introduction of the trifluoromethyl and halogen groups to these reductively dearomatized intermediates remains unachieved, most likely because of the sensitivity of these intermediates to oxidation in the presence of electrophilic reagents (35).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Cao

Cheng

Studer

2022

Science

View full text Add to dashboard Cite

Carbon-hydrogen (C−H) functionalization of pyridines is a powerful tool for the rapid construction and derivatization of many agrochemicals, pharmaceuticals, and materials. Because of the inherent electronic properties of pyridines, selective meta -C−H functionalization is challenging. Here, we present a protocol for highly regioselective meta -C−H trifluoromethylation, perfluoroalkylation, chlorination, bromination, iodination, nitration, sulfanylation, and selenylation of pyridines through a redox-neutral dearomatization-rearomatization process. The introduced dearomative activation mode provides a diversification platform for meta-selective reactions on pyridines and other azaarenes through radical as well as ionic pathways. The broad scope and high selectivity of these catalyst-free reactions render these processes applicable for late-stage functionalization of drugs.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Cao

Cheng

Studer

2022

Science

View full text Add to dashboard Cite

show abstract

“…Beyond these two approaches, there has been little progress over the past century, so the synthetic community turned to other versatile functional groups in place of halides. Iridium-catalyzed borylations and silylations are the most notable processes and are 3-selective for certain classes of substituted pyridines or through control with ligand architectures (20)(21)(22)(23)(24)(25)(26). Here, we present an alternative approach for pyridine halogenation using a ring-opening, halogenation, ring-closing strategy (Fig.…”

mentioning

confidence: 99%

Halogenation of the 3-position of pyridines through Zincke imine intermediates

Boyle

Levy

Lescure

et al. 2022

Science

View full text Add to dashboard Cite

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon–hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the nature of the halogen electrophile can modify the selectivity-determining step. Using this method, we produced a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

show abstract

“…The reaction afforded a mixture of mono- and ditrifluoromethylated products, and the directing group limited the structure of the substrates. Herein, we report the first 3-position-selective trifluoromethylation of pyridine rings based on nucleophilic activation . To do so, we focused on hydrosilylation for the nucleophilic activation of the pyridine rings (Scheme C).…”

mentioning

confidence: 99%

3-Position-Selective C–H Trifluoromethylation of Pyridine Rings Based on Nucleophilic Activation

2022

View full text Add to dashboard Cite

The first example of the 3-position-selective C(sp2)–H trifluoromethylation of pyridine rings was established. 3-Position-selective trifluoromethylation was achieved by the nucleophilic activation of pyridine and quinoline derivatives through hydrosilylation and successive electrophilic trifluoromethylation of the enamine intermediate. This reaction was applicable to perfluoroalkylation at the 3 position of the pyridine rings and late-stage trifluoromethylation of a bioactive molecule. Mechanistic studies indicated that the reaction proceeds via the formation of N-silyl enamine and trifluoromethylated enamine intermediates.

show abstract

C3-Selective Trifluoromethylthiolation and Difluoromethylthiolation of Pyridines and Pyridine Drugs via Dihydropyridine Intermediates

Cited by 63 publications

References 70 publications

Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Halogenation of the 3-position of pyridines through Zincke imine intermediates

3-Position-Selective C–H Trifluoromethylation of Pyridine Rings Based on Nucleophilic Activation

Contact Info

Product

Resources

About