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Catalytic Strategies to Convert 2-Halopyridines to 2-Alkylpyridines

Catalytic Strategies to Convert 2-Halopyridines to 2-Alkylpyridines. J. Miles Blackburn Roizen Group Duke University September 24 th , 2019 Content adapted from: Asian J. Org. Chem. 2019 , 8 , 920. 2-Alkylpyridines. Pyridine: most common heterocycle in bioactive molecules

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Catalytic Strategies to Convert 2-Halopyridines to 2-Alkylpyridines

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  1. Catalytic Strategies to Convert 2-Halopyridines to 2-Alkylpyridines J. Miles Blackburn Roizen Group Duke University September 24th, 2019 Content adapted from: Asian J. Org. Chem. 2019, 8, 920

  2. 2-Alkylpyridines • Pyridine: most common heterocycle in bioactive molecules • C(sp2)–C(sp3) linkages: three-dimensional complexity (under represented in synthetic libraries) • Cross-coupling technologies of nitrogen-containing heterocycles are often less efficient than with carbocyclic arenes • Lewis basic nitrogen atoms can coordinate to and deactivate catalysts • Pyridyl nucleophiles are often challenging to prepare, highly unstable, and rapidly decompose under standard cross-coupling reaction conditions • Availability and predictable reactivity of 2-halopyridines makes them attractive precursors for 2-alkylpyridines

  3. Challenges with Alkyl Nucleophiles • Strategies to avoid deleterious isomerization: • Use ligands/catalysts that facilitate rapid reductive elimination (i.e. bulky ligands) • Use rigid bidentate ligands so that catalysts cannot engage b-hydride elimination Badouin, ACIE, 2016, 55, 14793.

  4. Kumada-Corriu-TamaoReactions (Mg) with Aryl Fluorides Cornella, ACIE, 2018, 57, 9103.

  5. Recent Advances in the Negishi (Zn) Reaction with Secondary Nucleophiles PEPPSI: Pyridine-EnchancedPrecatalyst Preparation Stabilization and Initiation Tu, JOC, 2013, 78, 7463. Organ, Chem. Eur. J. 2016, 22, 14531.

  6. Recent Advances in the Negishi (Zn) Reaction with Secondary Nucleophiles Buchwald, OL, 2014, 16, 4638. Buchwald, ACIE, 2016, 55, 1849. Schoenebeck, ACIE, 2018, 57, 12573 Cherney, Organometallics 2019, 38, 97.

  7. 2-Alkylpyridines from Suzuki (B) and Stille (Sn) Reactions Molander, JOC, 2012, 79, 10399; OL, 2010, 12, 4876; OL, 2011, 13, 3956; OL, 2012, 14, 4458; JACS, 2012, 134, 16856. Biscoe, Nature Chem. 2013, 5, 607.

  8. 2-Alkylpyridines from Suzuki (B) and Stille (Sn) Reactions Roizen, OL, 2016, 18, 4440. Roizen, Chem. Commun. 2017, 53, 7270.

  9. Cross-Electrophile Couplings with Bpy-Type Ligands Gong, OL, 2012, 14, 3352. Weix, Synlett, 2014, 25, 233. Liu, Synth. Commun. 2014, 44, 2999. Molander, JOC, 2014, 79, 5771.

  10. Cross-Electrophile Couplings with Bpy-Type Ligands Weix, JOC, 2017, 82, 7085.

  11. Dual Photoredox/Nickel Catalysis Trifluoroborates: Molander, Science, 2014, 345, 433. Carboxylates: MacMillan, Doyle, Science, 2014, 345, 437. Silicates: Molander, JACS, 2016, 138, 475. Dihydropyridines: Molander, ACS Catal. 2016, 6, 8004. Alkyl bromides: MacMillan, JACS, 2016, 138, 8084. Sulfinates: Knauber, OL, 2017, 19, 6566. C(sp3)–H Bonds: MacMillan, Nature 2018, 560, 70.

  12. Photoredox Catalysis Promoted Hydroarylation Jui, Chem Sci. 2017, 8, 3121; Chem. Sci. 2017, 8, 7998; JACS, 2017, 139, 6582; JACS, 2018, 140, 15525; JACS, 2019, 141, 4147.

  13. Photoredox Catalysis Promoted Hydroarylation

  14. Catalytic Strategies to Convert 2-Halopyridines to 2-Alkylpyridines Asian J. Org. Chem. 2019, 8, 920

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