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Base-Controlled Regioselective Functionalization of Chloro-Substituted Quinolines
Valter E Murie1, Rodolfo H V Nishimura1,2, Larissa A Rolim3
1Núcleo de Pesquisas em Produtos Naturais e Sintéticos, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo , Av. do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
The Journal of Organic Chemistry
|December 15, 2017
Summary
Researchers developed new methods for synthesizing functionalized quinolines using selective metalation. These strategies offer convenient routes to bioactive quinoline derivatives, including potential chloroquine analogues.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
Background:
- Quinolines are important heterocyclic compounds with diverse biological activities.
- Developing efficient synthetic routes for functionalized quinolines is crucial for drug discovery.
Purpose of the Study:
- To develop novel methods for the regioselective synthesis of di- and trifunctionalized quinolines.
- To explore the utility of metal amides in functionalizing chloro-substituted quinolines.
- To provide convenient strategies for accessing bioactive quinoline derivatives.
Main Methods:
- Selective metalation of chloro-substituted quinolines using various metal amides (lithium diisopropylamide, lithium-magnesium amide, lithium-zinc amide).
- Reaction of metalated intermediates with different electrophiles.
- Density Functional Theory (DFT) calculations to rationalize regioselectivity.
Main Results:
- Achieved selective metalation at the C-3 position using lithium diisopropylamide at -70 °C.
- Obtained C-2 or C-8 functionalized quinoline derivatives regioselectively using lithium-magnesium and lithium-zinc amides.
- Demonstrated complementary metalation strategies for diverse quinoline functionalization.
Conclusions:
- Developed versatile and regioselective metalation methods for synthesizing functionalized quinolines.
- These methods provide convenient access to complex quinoline structures.
- The synthesized compounds serve as potential precursors for novel bioactive molecules, including chloroquine analogues.
