Switchable and Ring-Selective Hydrogenation of Naphthyridine Isomers
1Chemical Process Research and Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Organic Letters
|June 12, 2025
Summary
Selective hydrogenation of naphthyridines was achieved using distinct ruthenium or palladium catalysts. These methods offer predictable control over which ring is reduced, overcoming challenges in complex heterocyclic chemistry.
Area of Science:
- Organic Chemistry
- Catalysis
- Heterocyclic Chemistry
Background:
- Hydrogenation of heteroarenes with multiple reducible rings is challenging due to regioselectivity control issues.
- Naphthyridines are important heterocyclic compounds with diverse applications.
Purpose of the Study:
- To develop orthogonal procedures for the selective hydrogenation of [1,6]- and [1,7]-naphthyridines.
- To control regioselectivity in the reduction of naphthyridine rings.
Main Methods:
- Utilized a homogeneous ruthenium precatalyst, [Ru(p-cymene)I2]2, for selective hydrogenation.
- Employed a heterogeneous palladium catalyst for orthogonal selective hydrogenation.
- Investigated the effect of NaBArF4 (tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) on reaction activity.
Main Results:
- Achieved selective hydrogenation of [1,6]- and [1,7]-naphthyridines to their tetrahydronaphthyridine counterparts.
- Demonstrated tolerance to a wide range of substituents and functional groups.
- Mechanistic studies confirmed direct hydrogenation pathways for each catalyst system, ruling out product interconversion.
Conclusions:
- Developed two distinct catalytic protocols for the selective and predictable reduction of naphthyridine rings.
- Ruthenium-catalyzed hydrogenation selectivity is primarily governed by electronic effects.
- Palladium-catalyzed hydrogenation selectivity is influenced by a combination of steric and electronic factors.
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